Methods for preparing pyrimidine derivatives useful as protein kinase inhibitors

ABSTRACT

A method of preparing a compound represented by Structural Formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein the variables of Structural Formula (I) are as described in the specification and claims. Additionally, the present invention relates to compounds of Structural Formula (I), which are useful as inhibitors of protein kinase.

CROSS-REFERENCE

This application claims priority to U.S. Application No. 61/245,773,filed on Sep. 25, 2009. The entire contents of the aforementionedapplication are incorporated herein.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by a better understanding of the structure of enzymes and otherbiomolecules associated with diseases. One important class of enzymesthat has been the subject of intensive study is protein kinases.

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within the cell (see Hardie, G. and Hanks, S. TheProtein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.:1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases may be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids etc). Sequence motifs have beenidentified that generally correspond to each of these kinase families(See, for example, Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596;Knighton et al., Science 1991, 253, 407-414; Hiles et al, Cell 1992, 70,419-429; Kunz et al, Cell 1993, 73, 585-596; Garcia-Bustos et al, EMBOJ. 1994, 13, 2352-2361).

In general, protein kinases mediate intracellular signaling by effectinga phosphoryl transfer from a nucleoside triphosphate to a proteinacceptor that is involved in a signaling pathway. These phosphorylationevents act as molecular on/off switches that can modulate or regulatethe target protein biological function. These phosphorylation events areultimately triggered in response to a variety of extracellular and otherstimuli. Examples of such stimuli include environmental and chemicalstress signals (e.g., shock, heat shock, ultraviolet radiation,bacterial endotoxin, and H₂O₂), cytokines (e.g., interleukin-1 (IL-1)and tumor necrosis factor alpha (TNF-a), and growth factors (e.g.,granulocyte macrophage-colony stimulating factor (GM-CSF), andfibroblast growth factor (FGF)). An extracellular stimulus may affectone or more cellular responses related to cell growth, migration,differentiation, secretion of hormones, activation of transcriptionfactors, muscle contraction, glucose metabolism, control of proteinsynthesis, survival and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events as described above. These diseasesinclude, but are not limited to, cancer, autoimmune diseases,inflammatory diseases, bone diseases, metabolic diseases, neurologicaland neurodegenerative diseases, cardiovascular diseases, allergies andasthma, Alzheimer's disease and hormone related diseases. Accordingly,there has been a substantial effort in medicinal chemistry to findprotein kinase inhibitorsthat are effective as therapeutic agents.

The Polo-like kinases (Plk) belong to a family of serine/threoninekinases that are highly conserved across the species, ranging from yeastto man (reviewed in Lowery D M et al., Oncogene 2005, 24; 248-259). ThePlk kinases have multiple roles in cell cycle, including control ofentry into and progression through mitosis. Plk1 is the bestcharacterized of the Plk family members. Plk1 is widely expressed and ismost abundant in tissues with a high mitotic index. Protein levels ofPlk1 rise and peak in mitosis (Hamanaka, R et al., J Biol Chem 1995,270, 21086-21091). The reported substrates of Plk1 are all moleculesthat are known to regulate entry and progression through mitosis, andinclude CDC25C, cyclin B, p53, APC, BRCA2 and the proteasome. Plk1 isupregulated in multiple cancer types and the expression levels correlatewith severity of disease (Macmillan, J C et al., Ann Surg Oncol 2001, 8,729-740). Plk1 is an oncogene and can transform NIH-3T3 cells (Smith, MR et al., Biochem Biophys Res Commun 1997, 234, 397-405). Depletion orinhibition of Plk1 by siRNA, antisense, microinjection of antibodies, ortransfection of a dominant negative construct of Plk1 into cells,reduces proliferation and viability of tumour cells in vitro (Guan, R etal., Cancer Res 2005, 65, 2698-2704; Liu, X et al., Proc Natl Acad SciUSA 2003, 100, 5789-5794, Fan, Y et al., World J Gastroenterol 2005, 11,4596-4599; Lane, H A et al., J Cell Biol 1996, 135, 1701-1713). Tumourcells that have been depleted of Plk1 have activated spindle checkpointsand defects in spindle formation, chromosome alignment and separationand cytokinesis. Loss in viability has been reported to be the result ofan induction of apoptosis. In contrast, normal cells have been reportedto maintain viability on depletion of Plk1. In vivo knock down of Plk1by siRNA or the use of dominant negative constructs leads to growthinhibition or regression of tumours in xenograft models.

Plk2 is mainly expressed during the G1 phase of the cell cycle and islocalized to the centrosome in interphase cells. Plk2 knockout micedevelop normally, are fertile and have normal survival rates, but arearound 20% smaller than wild type mice. Cells from knockout animalsprogress through the cell cycle more slowly than in normal mice (Ma, Set al., Mol Cell Biol 2003, 23, 6936-6943). Depletion of Plk2 by siRNAor transfection of kinase inactive mutants into cells blocks centrioleduplication. Downregulation of Plk2 also sensitizes tumour cells totaxol and promotes mitotic catastrophe, in part by suppression of thep53 response (Burns T F et al., Mol Cell Biol 2003, 23, 5556-5571).

Plk3 is expressed throughout the cell cycle and increases from G1 tomitosis. Expression is upregulated in highly proliferating ovariantumours and breast cancer and is associated with a worse prognosis(Weichert, W et al., Br J Cancer 2004, 90, 815-821; Weichert, W et al.,Virchows Arch 2005, 446, 442-450). In addition to regulation of mitosis,Plk3 is believed to be involved in Golgi fragmentation during the cellcycle and in the DNA-damage response. Inhibition of Plk3 by dominantnegative expression is reported to promote p53-independent apoptosisafter DNA damage and suppresses colony formation by tumour cells (L1, Zet al., J Biol Chem 2005, 280, 16843-16850.

Plk4 is structurally more diverse from the other Plk family members.Depletion of this kinase causes apoptosis in cancer cells (L1, J et al.,Neoplasia 2005, 7, 312-323). Plk4 knockout mice arrest at E7.5 with ahigh fraction of cells in mitosis and partly segregated chromosomes(Hudson, J W et al., Current Biology 2001, 11, 441-446).

Molecules of the protein kinase family have been implicated in tumourcell growth, proliferation and survival. Accordingly, there is a greatneed to develop compounds useful as inhibitors of protein kinases. Theevidence implicating the Plk kinases as essential for cell division isstrong. Blockade of the cell cycle is a clinically validated approach toinhibiting tumour cell proliferation and viability.

A number of Plk kinase inhibitors have been reported in the art. See,for example, US 2009/0062292, US 2008/0167289, US 2006/004014, U.S. Pat.No. 6,806,272, U.S. Pat. No. 6,861,422, WO2009/040556, WO 2009/042711,and WO 2006/058876. Considering the potential of these Plk kinaseinhibitors for treating one or more of the aforementioned diseases, itwould be desirable to develop new efficient synthetic methods for suchinhibitors and for their derivatives.

SUMMARY OF TILE INVENTION

The present invention generally relates to a method of preparing acompound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —H, C₁₋₆ aliphatic, C₃₋₁₀ cycloaliphatic, C₆₋₁₀ aryl, 5-10membered heteroaryl, or 3-10 membered heterocyclyl, wherein each of saidaliphatic, cycloaliphatic, aryl, heteroaryl, and heterocyclyl groupsrepresented by R¹ is optionally and independently substituted with oneor more instances of J¹;

each R², R³, R⁴, and R⁵ is independently —H, halogen, cyano, C₁₋₆aliphatic, or C₃₋₁₀ cycloaliphatic, wherein each of said aliphatic andcycloaliphatic groups represented by R², R³, R⁴, and R⁵, respectively,is optionally and independently substituted with one or more instancesof J², J³, J⁴, and J⁵, respectively;

-   -   optionally, R² and R³, together with the carbon atom to which        they are attached, form a C₃₋₇cycloaliphatic ring that is        optionally substituted with one or more instances of J^(B);    -   optionally, R³ and R⁴, together with the carbon atoms to which        they are attached, form a C₃₋₇cycloaliphatic ring that is        optionally substituted with one or more instances of J^(B);    -   optionally, R⁴ and R⁵, together with the carbon atom to which        they are attached, form a C₃₋₇cycloaliphatic ring that is        optionally substituted with one or more instances of J^(B);

R⁶ is —H, C₁₋₆ aliphatic, C₃₋₁₀ cycloaliphatic, C₆₋₁₀ aryl, 5-10membered heteroaryl, or 3-10 membered heterocyclyl, wherein each of saidaliphatic, cycloaliphatic, aryl, heteroaryl, and heterocyclyl groupsrepresented by R⁶ is optionally and independently substituted with oneor more instances of J⁶;

R⁷ is —H, C₁₋₆ aliphatic optionally substituted with one or moreinstanced of J^(A), or C₃₋₈ cycloaliphatic optionally substituted withone or more instanced of J^(B); or, optionally R⁷, together with R¹ andthe nitrogen atom to which it is attached, forms a 5-7 memberedheterocyclic ring that is optionally substituted with one or moreinstances of J^(B); and

R⁸ is —H or R⁹;

R⁹ is C₁₋₆ aliphatic or C₃₋₈cycloaliphatic, wherein said aliphatic groupis independently and optionally substituted with one or more instancesof J^(A), and wherein said cycloaliphatic group is independently andoptionally substituted with one or more instances of J^(B);

each J¹ is independently T or C₁₋₆ aliphatic optionally substituted withone or more instances of T;

each of J², J³, J⁴, J⁵, and J⁶ is independently M, or C₁₋₆ aliphaticoptionally substituted with one or more instances of M;

each T is independently halogen, oxo, —NO₂, —CN, Q¹, —Z¹—H, or —Z²-Q²;

each Z¹ is independently a unit consisting of one or more groupsindependently selected from the group consisting of —NR—, —O—, —S—,—C(O)—, —C(═NR)—, —C(═NOR)—, and —SO₂N(R)—;

each Z² is independently a unit consisting of one or more groupsindependently selected from the group consisting of —NR—, —O—, —S—,—C(O)—, —C(═NR)—, —C(═NOR)—, —S(O)—, and —S(O)₂—;

each Q¹ is independently C₃₋₁₀ cycloaliphatic, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, or 3-10 membered heterocyclyl, wherein each Q¹ isindependently and optionally substituted with one or more instances ofJ^(Q);

each Q² is independently C₁₋₆ aliphatic, C₃₋₁₀ cycloaliphatic, C₆₋₁₀aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, or Q¹-Q¹,each of which is optionally and independently substituted with one ormore instances of J^(Q); or each Q², together with R and the nitrogenatom to which it is attached, optionally forms a 4-7 memberedheterocyclic ring optionally substituted with one or more instances ofJ^(B); and

each J^(Q) is independently M or C₁₋₆ aliphatic optionally substitutedwith one or more instances of M;

each M is independently halogen, oxo, —NO₂, —CN, —OR′, —SR′, —N(R′)₂,—COR′, —CO₂R′, —CONR′₂, —OCOR″, —OCON(R′)₂, —NRCOR′, —NRCO₂R′,—NRCON(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂, —NRSO₂R″, —NRSO₂N(R′)₂, C₃₋₁₀cycloaliphatic, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, or 5-10 memberedheteroaryl, wherein each of said cycloaliphatic, heterocyclyl, aryl andheteroaryl groups represented by M is optionally and independentlysubstituted with one or more instances of J^(B);

each R′ is independently —H or C₁₋₆ aliphatic, or each R, together withQ² and the nitrogen atom to which it is attached, optionally forms a 4-7membered heterocyclic ring optionally being substituted with one or moreinstances of J^(B);

each R′ is independently —H or C₁₋₆ aliphatic optionally substitutedwith one or more instances of J^(A); or two R′ groups, together with thenitrogen atom to which they are attached, form a 4-7 memberedheterocyclic ring optionally being substituted with one or moreinstances of J^(B);

each R″ is independently C₁₋₄ aliphatic optionally substituted with oneor more instances of J^(A);

each J^(A) is independently selected from the group consisting ofhalogen, oxo, —CN, —OH, —NH₂; —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄alkyl), C₃₋₇cycloalkyl, and C₃₋₇ cyclo(haloalkyl);

each J^(B) is independently selected from the group consisting ofhalogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄alkyl), and C₁-C₄ aliphatic that is optionally substituted with one ormore instances of J^(A); and

q is 0 or 1.

The method comprises the steps of:

a) reacting a compound represented by Structural Formula (A):

with HNR¹R⁷ under suitable conditions to form a compound represented byStructural

Formula (B):

wherein: R¹¹ is —NHR¹³, and R¹² is halogen; or R¹¹ is —OR¹⁴, and R¹² is—NO₂; and R¹³ is —H or R⁹; R¹⁴ is C₁₋₆ alkyl; and LG₁ is a suitableleaving group; andb) i) when R¹² is —NO₂, and R¹¹ is —OR⁴:

-   -   1) cyclizing the compound represented by Structural Formula (B)        under suitable cyclisation conditions to form a compound        represented by Structural Formula (II):

-   -   2) optionally reacting the compound represented by Structural        Formula (II) with R⁹-LG₂, wherein LG₂ is a suitable leaving        group, to form the compound represented by Structural Formula        (I), wherein R⁸ is other than —H; or

ii) when R¹² is halogen, and R¹¹ is —NHR¹³:

-   -   1) cyclizing the compound represented by Structural Formula (B)        under suitable cyclisation conditions to form the compound        represented by Structural Formula (I); and    -   2) optionally, when R¹³ is —H, reacting the compound produced        from step b), ii), 1) with R⁹-LG₂, wherein LG₂ is a suitable        leaving group, to form the compound represented by Structural        Formula (I) wherein R⁸ is other than —H.

The compounds represented by Structural Formula (I) can inhibit proteinkinases, such as Plk kinases (e.g., Plk1, Plk2, Plk3 and/or Plk4). See,for example, US 2009/0062292 and US 2008/0167289. The present inventioncan provide efficient synthetic methods for preparing such compoundsthat are useful as protein kinases inhibitors, particularly Plkinhibitors.

DETAILED DESCRIPTION OF THE INVENTION

The methods of the invention generally employ introduction of —NR¹R⁷into the pyrimidine ring of Structural Formula (I) prior to thecyclisation step to form the ring (e.g., peperazin-2-one ordiazepin-5-one) that is fused to the pyrimidine ring. Without beingbound to a particular theory, early amination, particularly for aryl andheteroaryl amines, such as aniline, prior to the cyclisation can bebeneficial for the convenience for purification processes of the finalcompounds. Generally, amines, especially aryl and heteroaryl amines, arepotentially hazardous. If such materials are employed at a later stage(e.g., anilination after the cyclisation) of the production line,purifying the final products from them can be cumbersome and costy,especially in a large scale production line. For example, losing someintermediate compounds during purification processes might be bettertolerable than losing some final products. Certain aspects of themethods of the invention are depicted below in schemes and preparativeexamples that follow. Unless otherwise indicated, all variables in thefollowing schemes are as defined herein.

The methods of the invention employ the step of: a) reacting a compoundrepresented by Structural Formula (A) with HNR¹R⁷ under suitableconditions to form a compound represented by Structural Formula (B):

wherein R¹¹ is —NHR¹³, and R¹² is halogen; or R¹¹ is —OR⁴, and R¹² is—NO₂; and R¹³ is —H or R⁹; R¹⁴ is C₁₋₆ alkyl; and LG, is a suitableleaving group. If R¹² is —NO₂, and R¹¹ is —OR¹⁴, the methods furthercomprise the step of cyclizing the compound represented by StructuralFormula (B) under suitable cyclisation conditions to form a compoundrepresented by Structural Formula (II):

and optionally further comprise the step of reacting the compoundrepresented by Structural Formula (II) with R⁹-LG₂, wherein LG₂ is asuitable leaving group, to form the compound represented by StructuralFormula (I), wherein R⁸ is other than —H. If R¹² is halogen, and R¹¹ is—NHR¹³, the methods further comprise the step of cyclizing the compoundrepresented by Structural Formula (B) under suitable cyclisationconditions to form the compound represented by Structural Formula (I);and, when R¹³ is —H, optionally further comprise the step of reactingthe compound produced from the prior cyslisation step with R⁹-LG₂ toform the compound represented by Structural Formula (I), wherein R⁸ isother than —H.

Suitable conditions for the amination step a) to introduce the —NR¹R⁷moiety into the pyrimidine ring can be found in the art, for example,Cywin et al., “Discovery of potent and selective PKC-theta inhibitors,”Bioorganic & Medicinal Chemistry Letters, 17(1), 225-230 (2007), andWO2006/108103. For example, the amination step can be performed in thepresence of a base (e.g., organic or inorganic base), such as NaHCO₃,NaCO₃, or a tertiary amine (e.g., DIPEA: N,N-diisopropylethylamine), inany suitable solvent system, e.g., peterolium ether and dichloromethan(DCM), or mixtures thereof. Alternatively, when R¹¹ is —OR⁴, and R¹² is—NO₂, the amination step can be performed simply by heating without abase.

Any suitable leaving group known in the art can be employed in theinvention for LG₁ and LG₂, respectively. One suitable example for eachLG₁ and LG₂ is halogen, such as —Cl, —Br or —I. Other suitable examplesof LG, include triflate (—OSO₂CF₃), tosylate (O-(p-toluenesulfonyl)),mesylate (—OSO₂ (CH₃)), lower alkyl sulfones, such as methylsulfone(—SO₂Me), etc. In one specific embodiment, LG₁ is —Cl; and LG₂ is —Cl,—Br, or —I.

Cyclisation between R¹¹ and R¹² to form the ring (e.g., peperazin-2-oneor diazepin-5-one) that is fused to the pyrimidine ring can be performedin any suitable condition known in the art. For example, suitablereaction conditions for reductive cyclisation between nitro and estergroups (when is R¹² is —NO₂, and R¹¹ is —OR¹⁴) can be found in US2008/0167289, US 2009/0062292, US 2006/004014, U.S. Pat. No. 6,861,422,U.S. Pat. No. 6,806,272, and US2008/0009482. For example, suitablereaction conditions for cyclisation between halogen and amide groups(when R¹² is halogen, and R¹¹ is —NHR¹³) can be found in US2008/0009482.

In one embodiment, R¹² is —NO₂, and R¹¹ is —OR¹⁴. In this embodiment,reductive cyclisation between the nitro and ester groups in compounds ofStructural Formula (B) is performed to produce compounds represented byStructural Formula (II). Any suitable reductive cyclisation conditionbetween nitro and ester groups known in the art can be employed in theinvention. In one specific embodiment, the reductive cyclisation isperformed as shown in Scheme 1:

The first step involves reduction of the nitro group under suitablereduction conditions, such as iron powder, SnCl₂, zinc powder,indium/HCl, or H₂/Pd to form a compound represented by StructuralFormula (L1). The second step involves cyclo-condensation between theamine and ester groups of Structural Formula (L1), resulting in thecompound represented by Structural Formula (II). Cyclo-condensationstypically occur in the presence of an acid or a base. In someembodiments, this two-step process occurs in situ. One example of an insitu condition involves treating the nitro compound (represented byStructural Formula (B1)) with iron powder in glacial acetic acid.

Optionally, as shown in Scheme 2, the compound represented by StructuralFormula (II) can further reacts with R⁹-LG₂, wherein LG₂ is a suitableleaving group, to form the compound represented by Structural Formula(I) wherein R⁸ is other than H:

Alternatively, compounds of Structural Formula (L1) can be firstfunctionalized to form compounds of Structural Formula (L2) which cansubsequently be cyclised to form compounds of Structural Formula (I)wherein R⁸ is other than H, as shown in Scheme 3:

In another embodiment, R¹² is halogen, such as —Br or —I, and R¹¹ is—NHR¹³. In this embodiment, cyclisation between halogen (e.g., —Br asexemplified in Scheme 4) and amide groups in a compound of StructuralFormula (B) (e.g., a compound of Structural Formula (B2) in Scheme 4) isperformed to produce the compound represented by Structural Formula (I),as shown in Scheme 4:

Any suitable cyclisation condition between halogen (e.g., —Br or —I) andamide groups known in the art can be employed in the invention. In onespecific embodiment, the cyclisation is performed under palladiumcatalysis, for example, using a suitable palladium catalyst (e.g., Pd₂(dba)₃, where “dba” is tris(dibenzylideneacetone)dipalladium) and asuitable base (e.g., Xantphos).

Optionally, when R¹³ is —H, the compound represented by StructuralFormula (I) wherein R¹³ is —H can further react with a suitablesource(s) for R⁹, e.g., R⁹-LG₂, wherein LG₂ is a suitable leaving group,to form the compound represented by Structural Formula (I), wherein R⁸is other than H.

The compounds of Structural Formula (A) can be prepared by any suitablemethod known in the art. In one embodiment, a compound of StructuralFormula (A) can be prepared via reacting a compound represented byStructural Formula (C) with a compound represented by Structural Formula(D) to form the compound represented by Structural Formula (A), whereinLG₃ is a suitable leaving group:

Any suitable leaving group known in the art can be employed in theinvention for LG₃. One suitable example for LG₃ is halogen, such as —Cl,—Br, or —I. Other suitable examples of LG₁ include triflate (—OSO₂CF₃),tosylate (O-(p-toluenesulfonyl)), mesylate (—OSO₂(CH₃)), lower alkylsulfones, such as methylsulfone (—SO₂Me), etc. In one specificembodiment, LG₃ is —Cl, —Br, or —I. In another specific embodiment, LG₃is —Cl.

Suitable conditions for the reaction of the compounds of Structuralformula (C) with the compounds of Structural Formula (D) to form thecompounds of Structural Formula (A) can be found in the art, forexample, US 2008/0062292, US 2008/0009482, and US 2008/0167289. In oneembodiment, the compounds of Structural Formula (A1) are formed as shownin Scheme 5 by reaction of a 5-nitro-2,4-dichloropyrimidine ofStructural Formula (D1) with an amine of Structural Formula (C1).Suitable conditions for this reaction can be found in the art, forexample, US 2008/0167289 and US2008/0009482. In one example, a compoundof Structural Formula (C1) is reacted with5-nitro-2,4-dichloropyrimidine in the presence of a base (e.g., organicor inorganic base), such as NaHCO₃, NaCO₃, or a tertiary amine (e.g.,DIPEA: N,N-diisopropylethylamine) in any suitable solvent system (e.g.,petroleum ether, dichloromethane (DCM), acetone, or mixtures thereof),optionally with heating.

In another embodiment, the compounds of Structural Formula (A2) areformed as shown in Scheme 6 by reaction of a5-bromo-2,4-dichloropyrimidine of Structural Formula (D2) with an amineof Structural Formula (C2). Suitable conditions for this reaction can befound in the art, for example, US 2008/0167289 and US2008/0009482. Forexample, the reaction is performed by heating in the presence of a base,such as triethylamine or N,N,diisopropylethylamine (DIPEA), in a polarorganic solvent, such as acetonitrile or ethanol.

Compounds of Structural Formula (C1) may also be obtained by reaction ofesters of an appropriately substituted 3-amino-propanoic acid (F1):

with a ketone or aldehyde, in the presence of a suitable reducing agent,such as, for example, sodium triacetoxyborohydride, as described in US2008/0009482. Compounds of Structural Formula (C2) may also be obtainedby reaction of amides of propenoic acid (G1) with a suitable amine, asdescribed in US 2008/0009482:

The non-hydrogen R⁶ group can generally be introduced during thepreparation of the compounds of Structural Formulae (A) and (B)(including compounds of Structural Formulae (B1) and (B2)), as discussedabove. Alternatively, the non-hydrogen R⁶ group can be introduced afterthe cyclisation step to form the ring (e.g., peperazin-2′-one ordiazepin-5-one) that is fused to the pyrimidine ring, as desired. Forexample, as shown in Scheme 7, compounds of Structural Formula (H) canreact with a suitable reagent known in the art as a source for thenon-hydrogen R⁶ group (e.g., a desired R⁶X, wherein X is halide, such asR⁶Br, R⁶Cl, etc.) to form compounds of Structural Formula (K).

In one specific embodiment, a method of the invention comprises StepsA1-C1 and optionally Step D1, of Scheme 8. In another specificembodiment, a method of the invention comprises Steps A2-C2 andoptionally Step D2, of Scheme 9. Steps A1 and A2 are as described abovein Schemes 5 and 6, respectively. Steps B1 and B2 are independently areas described above for the amination step a). Step C1 and optional StepD1 are each independently as described above in Scheme 1. Steps C2 andoptional Step D2 are each independently as described above in Scheme 4.

In one embodiment, the methods of the invention can be employed inpreparing the compounds represented by Structural Formula (I) orpharmaceutically acceptable salts thereof, wherein values of thevariables of Structural Formula (I) are as described below.

The first set of variables of Structural Formula (I) is as follows:

R¹ is —H, C₁₋₆ aliphatic, C₃₋₁₀ cycloaliphatic, C₆₋₁₀ aryl, 5-10membered heteroaryl, or 3-10 membered heterocyclyl, wherein each of saidaliphatic, cycloaliphatic, aryl, heteroaryl, and heterocyclyl groupsrepresented by R¹ is optionally and independently substituted with oneor more instances of J₁. Specifically, R¹ is optionally substituted C₁₋₆aliphatic, optionally substituted C₆₋₁₀ aryl, or optionally substituted5-10 membered heteroaryl. Specifically, R¹ is optionally substitutedC₆₋₁₀ aryl or optionally substituted 5-10 membered heteroaryl. Morespecifically, R¹ is optionally substituted C₆₋₁₀ aryl or optionallysubstituted 5-6 membered heteroaryl. More specifically, R¹ is optionallysubstituted phenyl or optionally substituted 5-6 membered heteroaryl.More specifically, R¹ is optionally substituted phenyl.

Each of R², R³, R⁴, and R⁵ is independently —H, halogen, cyano, C₁₋₆aliphatic, or C₃₋₁₀ cycloaliphatic, wherein each of said aliphatic andcycloaliphatic groups represented by R², R³, R⁴, and R⁵, respectively,is optionally and independently substituted with one or more instancesof J², J³, J⁴, and J⁵, respectively. Optionally, R² and R³, togetherwith the carbon atom to which they are attached, form a C₃₋₇cycloaliphatic ring that is optionally substituted with one or moreinstances of J^(B). Optionally, R³ and R⁴, together with the carbonatoms to which they are attached, form a C₃₋₇cycloaliphatic ring that isoptionally substituted with one or more instances of J^(B). Optionally,R⁴ and R⁵, together with the carbon atom to which they are attached,form, a C₃₋₇ cycloaliphatic ring that is optionally substituted with oneor more instances of J^(B).

Specifically, each of R², R³, R⁴ and R⁵ is independently —H, halogen,optionally substituted C₁₋₆ aliphatic, or optionally substitutedC₃₋₇cycloaliphatic; or optionally R² and R³, R³ and R⁴, and R⁴ and R⁵,respectively, together with the atom to which they are bound,independently form an optionally substituted C₃₋₇ cycloaliphatic ring.Specifically, each of R², R³, R⁴, and R⁵ is independently —H, halogen,optionally substituted C₁₋₆ aliphatic; or optionally R² and R³, togetherwith the carbon atom to which they are attached, form an optionallysubstituted C₃₋₆ cycloalkyl ring. Specifically, each of R², R³, R⁴ andR⁵ is independently —H, or optionally substituted C₁₋₆ alkyl; oroptionally R² and R³, together with the atom to which they are bound,form an optionally substituted C₃₋₇ cycloalkyl ring. Specifically, eachof R², R³, R⁴ and R⁵ is independently —H, or optionally substituted C₁₋₆alkyl; or optionally R² and R³, together with the atom to which they arebound, form an optionally substituted C₃₋₆cycloalkyl ring. Morespecifically, R² is —H or C₁₋₃ alkyl; R³ is C₁₋₃alkyl; R⁴ is —H orC₁₋₃alkyl; and R⁵ is —H or C₁₋₃alkyl. More specifically, R² and R³together with the atom to which they are bound form a C₃₋₇ cycloalkylring; R⁴ is —H or C₁₋₃alkyl; and R⁵ is —H or C₁₋₃alkyl. Morespecifically, R² is —H or C₁₋₃alkyl; R³ is C₁₋₃alkyl; R⁴ is —H; and R⁵is —H. More specifically, R² and R³ together with the atom to which theyare bound form a C₃₋₇cycloalkyl ring; R⁴ is —H; and R⁵ is —H.

R⁶ is —H, C₁₋₆ aliphatic, C₃₋₁₀ cycloaliphatic, C₆₋₁₀ aryl, 5-10membered heteroaryl, or 3-10 membered heterocyclyl, wherein each of saidaliphatic, cycloaliphatic, aryl, heteroaryl, and heterocyclyl groupsrepresented by R⁶ is optionally and independently substituted with oneor more instances of J⁶. Specifically, R⁶ is —H, optionally substitutedC₁₋₆ aliphatic, optionally substituted C₃₋₇ cycloaliphatic, optionallysubstituted 4-7 membered heterocyclyl, optionally substituted phenyl, oroptionally substituted 5-6 membered heteroaryl. Specifically, R⁶ is —H,optionally substituted C₁₋₆ aliphatic, optionally substituted C₃₋₇cycloaliphatic, or optionally substituted 4-7 membered heterocyclyl.Specifically, R⁶ is —H, optionally substituted C₁₋₆ aliphatic oroptionally substituted C₃₋₇ cycloaliphatic. Specifically, R⁶ is —H,optionally substituted C₁₋₆ alkyl, or optionally substitutedC₃₋₇cycloalkyl. Specifically, R⁶ is —H, optionally substituted C₁₋₆alkyl, or optionally substituted C₃₋₆cycloalkyl. More specifically, R⁶is optionally substituted C₃₋₆cycloalkyl. Even more specifically, R⁶ iscyclopentyl.

R⁷ is —H, or a C₁₋₆ aliphatic or C₃₋₈cycloaliphatic group optionallysubstituted with one or more instanced of J^(A), or, optionally R⁷,together with R¹ and the nitrogen atom to which it is attached, forms a4-7 membered heterocyclic ring that is optionally being substituted withone or more instances of J^(B). Specifically, the heterocyclic ringformed with R¹ and R⁷ is 5-6 membered. Specifically, R⁷ is —H, oroptionally substituted C₁₋₆ aliphatic. More specifically, R⁷ is —H, orC₁₋₆ alkyl. Even more specifically, R⁷ is —H.

R⁸ is —H or R⁹.

R⁹ is C₁₋₆ aliphatic or C₃₋₈ cycloaliphatic, wherein said aliphaticgroup is independently and optionally substituted with one or moreinstances of J^(A), and wherein said cycloaliphatic group isindependently and optionally substituted with one or more instances ofJ^(B);

Specifically, said aliphatic and cycloaliphatic are independently alkyland cycloalkyl, respectively.

Specifically, R⁸ is —H, optionally substituted C₁₋₆ alkyl,C₃₋₇cycloalkyl, or C₃₋₇ cyclo(haloalkyl). Specifically, R⁸ is —H oroptionally substituted C₁₋₆ aliphatic. Specifically, R⁸ is —H oroptionally substituted C₁₋₁₆ alkyl. Specifically, R⁸ is —H, C₁₋₆ alkylor C₁₋₆haloalkyl. Specifically, R⁸ is —H or C₁₋₆ alkyl.

Each J¹ is independently T or C₁₋₆ aliphatic optionally substituted withone or more instances of T.

Each of J², J³, J⁴, J⁵, and J⁶ is independently M, or C₁₋₆ aliphaticoptionally substituted with one or more instances of M.

Each T is independently halogen, oxo, —NO₂, —CN, Q¹, —Z¹—H¹ or —Z²-Q².Specifically, each T is halogen, cyano, Q¹, —N(R)H, —OH, —CO₂H,—C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H, —N(R)SO₂N(R)H,—S(O)₂Q², —N(R)Q², —OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q²,—N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², —N(R)C(O)N(R)Q², —SO₂N(R)Q²,—N(R)SO₂Q², or —N(R)SO₂N(R)Q².

More specifically, each T is halogen, cyano, —N(R)H, —OH, —CO₂H,—C(O)N(R)H, —OC(O)N(R)H, —N(R)Q², —OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q²,—N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², or—N(R)C(O)N(R)Q².

Each M is independently halogen, oxo, —NO₂, —CN, —OR′, —SR′, —N(R′)₂,—COR, —CO₂R¹, —CONR₁₂, —OCOR″, —OCON(R′)₂, —NRCOR′, —NRCO₂R′,—NRCON(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂, —NRSO₂R″, —NRSO₂N(R′)₂, C₃₋₁₀cycloaliphatic, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, or 5-10 memberedheteroaryl, wherein each of said cycloaliphatic, heterocyclyl, aryl andheteroaryl groups represented by M is optionally and independentlysubstituted with one or more instances of J^(B).

Each Z¹ is independently a unit consisting of one or more groups (e.g.,up to four groups) independently selected from the group consisting of—NR—, —O—, —S—, —C(O)—, —C(═NR)—, —C(═NOR)—, and —SO₂N(R)—.Specifically, each Z¹ is independently —N(R)—, —O—, —CO₂—, —C(O)N(R)—,—OC(O)N(R)—, —N(R)CO₂—, —N(R)C(O)N(R)—, —C(O)N(R)CO₂—, —SO₂N(R)—, or—N(R)SO₂N(R)—.

Each Z² is independently a unit consisting of one or more groupsindependently selected from the group consisting of —NR—, —O—, —S—,—C(O)—, —C(═NR)—, —C(═NOR)—, —S(O)—, and —S(O)₂—. Specifically, each Z²is independently —N(R)—, —O—, —CO₂—, —OC(O)—, —C(O)N(R)—, —N(R)C(O)—,—OC(O)N(R)—, —N(R)CO₂—, —N(R)C(O)N(R)—, —C(O)N(R)CO₂—, —S(O)₂—,—SO₂N(R)—, —N(R)SO₂—, or —N(R)SO₂N(R)—.

Each Q¹ is independently C₃₋₁₀ cycloaliphatic, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, or 3-10 membered heterocyclyl, wherein each Q¹ isindependently and optionally substituted with one or more instances ofJ^(Q). Specifically, each Q¹ is independently optionally substitutedC₃₋₇cycloalkyl, optionally substituted phenyl, optionally substituted5-6 membered heteroaryl, or optionally substituted 4-7 memberedheterocyclyl. More specifically, each Q¹ is independently optionallysubstituted C₃₋₇cycloalkyl, optionally substituted phenyl, optionallysubstituted 5-6 membered heteroaryl, or optionally substituted 4-7membered heterocyclyl.

Each Q² is independently C₁₋₆ aliphatic, C₃₋₁₀ cycloaliphatic, C₆₋₁₀aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, or Q¹-Q¹,each of which is optionally and independently substituted with one ormore instances of J^(Q); or each Q², together with R and the nitrogenatom to which is attached, optionally forms a 4-7 membered heterocyclicring optionally being substituted with one or more instances of J^(B).Specifically, each Q² is independently optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₇cycloalkyl, optionally substitutedphenyl, optionally substituted 5-6 membered heteroaryl, or optionallysubstituted 4-7 membered heterocyclyl, or each Q², together with R andthe nitrogen atom to which it is attached, optionally and independentlyforms an optionally substituted 4-7 membered heterocyclic ring.

Each J^(Q) is independently M or C₁₋₆ aliphatic optionally substitutedwith one or more instances of M. Specifically, values of J^(Q) for eachof the C₃₋₇cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocyclyl groups represented by Q¹ independently include halogen,oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄ alkyl),C₁-C₄ alkyl, C₁-C₄ haloalkyl; C₁-C₄ cyanoalkyl, C₁-C₄ aminoalkyl, C₁-C₄hydroxyalkyl, and C₂-C₄ alkoxyalkyl. Specifically, values of J⁹ for theC₁₋₆ aliphatic (e.g., C₁₋₆ alkyl) represented by Q² include halogen,oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), and —O(C₁-C₄alkyl). Values of J^(Q) for each of the cycloalkyl, aryl, heteroaryl,and heterocyclyl groups represented by Q² independently include halogen,oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄ alkyl),C₁-C₄ alkyl, C₁-C₄ haloalkyl; C₁-C₄ cyanoalkyl, C₁-C₄ aminoalkyl, C₁-C₄hydroxyalkyl, and C₂-C₄ alkoxyalkyl.

Each R is independently —H or C₁₋₆ aliphatic, or each R, together withQ² and the nitrogen atom to which it is attached, optionally forms a 4-7membered heterocyclic ring optionally substituted with one or moreinstances of J^(B). Specifically, the C₁₋₄ aliphatic group is C₁₋₄alkyl. Specifically, each R is independently —H, —CH₃ or —CH₂CH₃, oreach R, together with Q² and the nitrogen atom to which it is attached,optionally forms a 4-7 membered heterocyclic ring optionally substitutedwith one or more instances of J^(B).

Each R′ is independently —H or C₁₋₆ aliphatic optionally substitutedwith one or more instances of J^(A); or two R′ groups, together with thenitrogen atom to which they are attached, form a 4-7 memberedheterocyclic ring optionally being substituted with one or moreinstances of J^(B). Specifically, the C₁₋₄ aliphatic group is C₁₋₄alkyl.

Each R″ is independently C₁₋₄ aliphatic optionally substituted with oneor more instances of J^(A). Specifically, the C₁₋₄ aliphatic group isC₁₋₄alkyl.

Each J^(A) is independently selected from the group consisting ofhalogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄alkyl), C₃₋₇cycloalkyl, and C₃₋₇ cyclo(haloalkyl).

Each J^(B) is independently selected from the group consisting ofhalogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄alkyl), and C₁-C₄ aliphatic that is optionally substituted with one ormore instances of J^(A).

A second set of variables of Structural Formula (I) is as follows:

R⁶ is —H, optionally substituted C₁₋₆ aliphatic, optionally substitutedC₃₋₇ cycloaliphatic, optionally substituted 3-7 membered heterocyclyl,optionally substituted phenyl, or optionally substituted 5-6 memberedheteroaryl.

R⁷ is —H or optionally substituted C₁₋₆ aliphatic

R⁸ is —H or optionally substituted C₁₋₆ aliphatic.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A third set of variables of Structural Formula (I) is as follows:

R¹ is optionally substituted C₁₋₆ aliphatic, optionally substitutedC₆₋₁₀ aryl, or optionally substituted 5-10 membered heteroaryl.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A fourth set of variables of Structural Formula (I) is as follows:

R⁷ is —H or optionally substituted C₁₋₆ aliphatic.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A fifth set of variables of Structural Formula (I) is as follows:

R¹ is optionally substituted C₁₋₆ aliphatic, optionally substitutedC₆₋₁₀ aryl, or optionally substituted 5-10 membered heteroaryl.

R⁷ is —H or optionally substituted C₁₋₆ aliphatic.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A sixth set of variables of Structural Formula (I) is as follows:

R⁶ is —H, optionally substituted C₁₋₆ aliphatic, optionally substitutedC₃₋₇ cycloaliphatic, optionally substituted 4-7 membered heterocyclyl,optionally substituted phenyl, or optionally substituted 5-6 memberedheteroaryl.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A seventh set of variables of Structural Formula (I) is as follows:

Values of R¹ and R⁷, wherever applicable, are independently as describedabove in the second, third, fourth, or fifth set of variables ofStructural Formula (I).

R⁶ is —H, optionally substituted C₁₋₆ aliphatic, optionally substitutedC₃₋₇ cycloaliphatic, optionally substituted 4-7 membered heterocyclyl,optionally substituted phenyl, or optionally substituted 5-6 memberedheteroaryl.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

An eighth set of variables of Structural Formula (I) is as follows:

Each of R², R³, R⁴ and R⁵ is independently —H, halogen, optionallysubstituted C₁₋₆ aliphatic, or optionally substitutedC₃₋₇cycloaliphatic; or optionally R² and R³, R³ and R⁴, and R⁴ and R⁵,respectively, together with the atom to which they are bound,independently form an optionally substituted C₃₋₇cycloaliphatic ring.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A ninth set of variables of Structural Formula (I) is as follows:

Values of R¹, R⁶ and R⁷, wherever applicable, are independently asdescribed above in the second, third, fourth, fifth, sixth, or seventhset of variables of Structural Formula (I).

Each of R², R³, R⁴ and R⁵ is independently —H, halogen, optionallysubstituted C₁₋₆ aliphatic, or optionally substitutedC₃₋₇cycloaliphatic; or optionally R² and R³, R³ and R⁴, and R⁴ and R⁵,respectively, together with the atom to which they are bound,independently form an optionally substituted C₃₋₇cycloaliphatic ring.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A tenth set of variables of Structural Formula (I) is as follows:

R⁸ is —H or optionally substituted C₁₋₆ aliphatic.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

An eleventh set of variables of Structural Formula (I) is as follows:

Values of R¹, R², R³, R⁴, R⁵, R⁶ and R⁷, wherever applicable, areindependently as described above in the second, third, fourth, fifth,sixth, seventh, eighth, or ninth set of variables of Structural Formula(I).

R⁸ is —H or optionally substituted C₁₋₆ aliphatic.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A twelfth set of variables of Structural Formula (I) is as follows:

Each Z¹ is independently —N(R)—, —O—, —S—, —CO₂—, —C(O)N(R)—,—OC(O)N(R)—, —N(R)CO₂—, —N(R)C(O)N(R)—, —C(O)N(R)CO₂—, —SO₂N(R)—, or—N(R)SO₂N(R)—.

Each Z² is independently —N(R)—, —O—, —S—, —CO₂—, —OC(O)—, —C(O)N(R)—,—N(R)C(O)—, —OC(O)N(R)—, —N(R)CO₂—, —N(R)C(O)N(R)—, —C(O)N(R)CO₂—,—S(O)₂—, —SO₂N(R)—, —N(R)SO₂—, or —N(R)SO₂N(R)—.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A thirteenth set of variables of Structural Formula (I) is as follows:

Values of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸, wherever applicable, areindependently as described above in the second, third, fourth, fifth,sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth set ofvariables of Structural Formula (I).

Each Z¹ is independently —N(R)—, —O—, —S—, —CO₂—, —C(O)N(R)—,—OC(O)N(R)—, —N(R)CO₂—, —N(R)C(O)N(R)—, —C(O)N(R)CO₂—, —SO₂N(R)—, or—N(R)SO₂N(R)—.

Each Z² is independently —N(R)—, —O—, —S—, —CO₂—, —OC(O)—, —C(O)N(R)—,—N(R)C(O)—, —OC(O)N(R)—, —N(R)CO₂—, —N(R)C(O)N(R)—, —C(O)N(R)CO₂—,—S(O)₂—, —SO₂N(R)—, —N(R)SO₂—, or —N(R)SO₂N(R)—.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A fourteenth set of variables of Structural Formula (I) is as follows:

R¹ is C₁₋₄ alkyl substituted with Q¹ and optionally further substitutedwith one or more substituents independently selected from the groupconsisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl),and —O(C₁-C₄ alkyl). Alternatively, R¹ is C₆₋₁₀ aryl or 5-6 memberedheteroaryl, each optionally and independently substituted with one ormore substituents independently selected from the group consisting of Tand C₁₋₆ aliphatic optionally substituted with one or more instances ofT; and wherein each T is halogen, cyano, Q¹, —N(R)H, —OH, —SH, —CO₂H,—C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H, —N(R)SO₂N(R)H,—S(O)₂Q², —N(R)Q², —OQ², —SQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q²,—N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², —N(R)C(O)N(R)Q²,—SO₂N(R)Q², —N(R)SO₂Q², or —N(R)SO₂N(R)Q². Specifically, R¹ is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of T and C₁₋₆ aliphatic optionallysubstituted with one or more instances of T; and wherein each T ishalogen, cyano, —N(R)H, —OH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H, —N(R)Q²,—OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q²,—OC(O)N(R)Q², —C(O)N(R)CO₂Q², or —N(R)C(O)N(R)Q².

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A fifteenth set of variables of Structural Formula (I) is as follows:

R¹ is C₁₋₄alkyl substituted with Q¹ and optionally further substitutedwith one or more substituents independently selected from the groupconsisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl),and —O(C₁-C₄ alkyl). Alternatively, R¹ is C₆₋₁₀ aryl or 5-6 memberedheteroaryl, each optionally and independently substituted with one ormore substituents independently selected from the group consisting of Tand C₁₋₆ aliphatic optionally substituted with one or more instances ofT; and wherein each T is halogen, cyano, Q¹, —N(R)H, —OH, —SH, —CO₂H,—C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H, —N(R)SO₂N(R)H,—S(O)₂Q², —N(R)Q², —OQ², —SQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q²,—N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², —N(R)C(O)N(R)Q²,—SO₂N(R)Q², —N(R)SO₂Q², or —N(R)SO₂N(R)Q². Specifically, R¹ is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of T and C₁₋₆ aliphatic optionallysubstituted with one or more instances of T; and wherein each T ishalogen, cyano, —N(R)H, —OH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H, —N(R)Q²,—OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q²,—OC(O)N(R)Q², —C(O)N(R)CO₂Q², or —N(R)C(O)N(R)Q².

R⁷ is —H, or optionally substituted C₁₋₆ aliphatic.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A sixteenth set of variables of Structural Formula (I) is as follows:

R¹ is C₁₋₄alkyl substituted with Q¹ and optionally further substitutedwith one or more substituents independently selected from the groupconsisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl),and —O(C₁-C₄ alkyl). Alternatively, R¹ is C₆₋₁₀ aryl or 5-6 memberedheteroaryl, each optionally and independently substituted with one ormore substituents independently selected from the group consisting of Tand C₁₋₆ aliphatic optionally substituted with one or more instances ofT; and wherein each T is halogen, cyano, Q¹, —N(R)H, —OH, —SH, —CO₂H,—C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H, —N(R)SO₂N(R)H,—S(O)₂Q², —N(R)Q², —OQ², —SQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q²,—N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², —N(R)C(O)N(R)Q²,—SO₂N(R)Q², —N(R)SO₂Q², or —N(R)SO₂N(R)Q². Specifically, R¹ is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of T and C₁₋₆ aliphatic optionallysubstituted with one or more instances of T; and wherein each T ishalogen, cyano, —N(R)H, —OH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H, —N(R)Q²,—OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q²,—OC(O)N(R)Q², —C(O)N(R)CO₂Q², or —N(R)C(O)N(R)Q².

R⁶ is —H, optionally substituted C₁₋₆ aliphatic, optionally substitutedC₃₋₇ cycloaliphatic, optionally substituted 4-7 membered heterocyclyl,optionally substituted phenyl, or optionally substituted 5-6 memberedheteroaryl.

R⁷ is —H, or optionally substituted C₁₋₆ aliphatic.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A seventeenth set of variables of Structural Formula (I) is as follows:

R¹ is C₁₋₄ alkyl substituted with Q¹ and optionally further substitutedwith one or more substituents independently selected from the groupconsisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl),and —O(C₁-C₄ alkyl). Alternatively, R¹ is C₆₋₁₀ aryl or 5-6 memberedheteroaryl, each optionally and independently substituted with one ormore substituents independently selected from the group consisting of Tand C₁₋₆ aliphatic optionally substituted with one or more instances ofT; and wherein each T is halogen, cyano, Q¹, —N(R)H, —OH, —SH, —CO₂H,—C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H, —N(R)SO₂N(R)H,—S(O)₂Q², —N(R)Q², —OQ², —SQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q²,—N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², —N(R)C(O)N(R)Q²,—SO₂N(R)Q², —N(R)SO₂Q², or —N(R)SO₂N(R)Q². Specifically, R¹ is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of T and C₁₋₆ aliphatic optionallysubstituted with one or more instances of T; and wherein each T ishalogen, cyano, —N(R)H, —OH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H, —N(R)Q²,—OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q²,—OC(O)N(R)Q², —C(O)N(R)CO₂Q², or —N(R)C(O)N(R)Q².

Each of R², R³, R⁴ and R⁵ is independently —H, halogen, optionallysubstituted C₁₋₆ aliphatic, or optionally substitutedC₃₋₇cycloaliphatic; or optionally R² and R³, R³ and R⁴, and R⁴ and R⁵,respectively, together with the atom to which they are bound,independently form an optionally substituted C₃₋₇ cycloaliphatic ring.

R⁶ is —H, optionally substituted C₁₋₆ aliphatic, optionally substitutedC₃₋₇ cycloaliphatic, optionally substituted 3-7 membered heterocyclyl,optionally substituted phenyl, or optionally substituted 5-6 memberedheteroaryl.

R⁷ is —H, or optionally substituted C₁₋₆ aliphatic.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

An eighteenth set of variables of Structural Formula (I) is as follows:

R¹ is C₁₋₄ alkyl substituted with Q¹ and optionally further substitutedwith one or more substituents independently selected from the groupconsisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl),and —O(C₁-C₄ alkyl). Alternatively, R¹ is C₆₋₁₀ aryl or 5-6 memberedheteroaryl, each optionally and independently substituted with one ormore substituents independently selected from the group consisting of Tand C₁₋₆ aliphatic optionally substituted with one or more instances ofT; and wherein each T is halogen, cyano, Q¹, —N(R)H, —OH, —SH, —CO₂H,—C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H, —N(R)SO₂N(R)H,—S(O)₂Q², —N(R)Q², —OQ², —SQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q²,—N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², —N(R)C(O)N(R)Q²,—SO₂N(R)Q², —N(R)SO₂Q², or —N(R)SO₂N(R)Q². Specifically, R¹ is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of T and C₁₋₆ aliphatic optionallysubstituted with one or more instances of T; and wherein each T ishalogen; cyano, —N(R)H, —OH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H, —N(R)Q²,—OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q²,—OC(O)N(R)Q², —C(O)N(R)CO₂Q², or —N(R)C(O)N(R)Q².

Each of R², R³, R⁴ and R⁵ is independently —H, halogen, optionallysubstituted C₁₋₆ aliphatic, or optionally substitutedC₃₋₇cycloaliphatic; or optionally R² and R³, R³ and R⁴, and R⁴ and R⁵,respectively, together with the atom to which they are bound,independently form an optionally substituted C₃₋₇cycloaliphatic ring.

R⁶ is —H, or optionally substituted C₁₋₆ aliphatic, optionallysubstituted C₃₋₇ cycloaliphatic, optionally substituted 3-7 memberedheterocyclyl, optionally substituted phenyl, or optionally substituted5-6 membered heteroaryl.

R⁷ is —H, or optionally substituted C₁₋₆ aliphatic.

R⁸ is —H, or optionally substituted C₁₋₆ aliphatic.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A nineteenth set of variables of Structural Formula (I) is as follows:

R¹ is C₁₋₄ alkyl substituted with Q¹ and optionally further substitutedwith one or more substituents independently selected from the groupconsisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₆H, —CO₂ (C₁-C₄ alkyl),and —O(C₁-C₄ alkyl). Alternatively, R¹ is C₆₋₁₀ aryl or 5-6 memberedheteroaryl, each optionally and independently substituted with one ormore substituents independently selected from the group consisting of Tand C₁₋₆ aliphatic optionally substituted with one or more instances ofT; and wherein each T is halogen, cyano, Q¹, —N(R)H, —OH, —SH, —CO₂H,—C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H, —N(R)SO₂N(R)H,—S(O)₂Q², —N(R)Q², —OQ², —SQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q²,—N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², —N(R)C(O)N(R)Q²,—SO₂N(R)Q², —N(R)SO₂Q², or —N(R)SO₂N(R)Q². Specifically, R¹ is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of T and C₁₋₆ aliphatic optionallysubstituted with one or more instances of T; and wherein each T ishalogen, cyano, —N(R)H, —OH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H, —N(R)Q²,—OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q²,—OC(O)N(R)Q², —C(O)N(R)CO₂Q², or —N(R)C(O)N(R)Q².

Each of R², R³, R⁴ and R⁵ is independently —H, halogen, optionallysubstituted C₁₋₆ aliphatic, or optionally substitutedC₃₋₇cycloaliphatic; or optionally R² and R³, R³ and R⁴, and R⁴ and R⁵,respectively, together with the atom to which they are bound,independently form an optionally substituted C₃₋₇cycloaliphatic ring.

R⁶ is —H, optionally substituted C₁₋₆ aliphatic, optionally substitutedC₃₋₇ cycloaliphatic, optionally substituted 3-7 membered heterocyclyl,optionally substituted phenyl, or optionally substituted 5-6 memberedheteroaryl.

R⁷ is —H, or C₁₋₆ alkyl.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A twentieth set of variables of Structural Formula (I) is as follows:

Values, including specific values, of R¹, R², R³, R⁴, R⁵, and R⁶ areindependently as described above in any set of fourteenth throughnineteenth sets of variables of Structural Formula (I).

R⁷ is —H.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A twenty first set of variables of Structural Formula (I) is as follows:

Values, including specific values, of R¹, R², R³, R⁴, and R⁵ areindependently as described above in any set of fourteenth throughnineteenth sets of variables of Structural Formula (I).

R⁶ is —H, optionally substituted C₁₋₆ alkyl, or optionally substitutedC₃₋₇ cycloalkyl.

R⁷ is —H, or C₁₋₆ alkyl. Specifically, R⁷ is —H.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A twenty second set of variables of Structural Formula (I) is asfollows:

Values, including specific values, of R¹, R², R³, R⁴, and R⁵ areindependently as described above in any set of fourteenth throughnineteenth sets of variables of Structural Formula (I).

R⁶ is —H, optionally substituted C₁₋₆ alkyl, or optionally substitutedC₃₋₇ cycloalkyl.

R⁷ is —H, or C₁₋₆ alkyl. Specifically, R⁷ is —H.

R⁸ is —H or C₁₋₆ alkyl.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A twenty third set of variables of Structural Formula (I) is as follows:

R¹ is C₁₋₄ alkyl substituted with Q¹ and optionally further substitutedwith one or more substituents independently selected from the groupconsisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl),and —O(C₁-C₄ alkyl). Alternatively, R¹ is C₆₋₁₀ aryl or 5-6 memberedheteroaryl, each optionally and independently substituted with one ormore substituents independently selected from the group consisting of Tand C₁₋₆ aliphatic optionally substituted with one or more instances ofT; and wherein each T is halogen, cyano, Q¹, —N(R)H, —OH, —SH, —CO₂H,—C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H, —N(R)SO₂N(R)H,—S(O)₂Q², —N(R)Q², —OQ², —SQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q²,—N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², —N(R)C(O)N(R)Q²,—SO₂N(R)Q², —N(R)SO₂Q², or —N(R)SO₂N(R)Q². Specifically, R¹ is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of T and C₁₋₆ aliphatic optionallysubstituted with one or more instances of T; and wherein each T ishalogen, cyano, —N(R)H, —OH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H, —N(R)Q²,—OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q²,—OC(O)N(R)Q², —C(O)N(R)CO₂Q², or —N(R)C(O)N(R)Q².

Each of R², R³, R⁴ and R⁵ is independently —H, or optionally substitutedC₁₋₆ alkyl; or optionally R² and R³, together with the atom to whichthey are bound, form an optionally substituted C₃₋₇cycloalkyl ring.

R⁶ is —H, optionally substituted C₁₋₆ alkyl, or optionally substitutedC₃₋₇ cycloalkyl.

R⁷ is —H, or C₁₋₆ alkyl.

R⁸ is —H or C₁₋₆ alkyl.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A twenty fourth set of variables of Structural Formula (I) is asfollows:

R¹ is C_(—) ₄ alkyl substituted with Q¹ and optionally furthersubstituted with one or more substituents independently selected fromthe group consisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), and —O(C₁-C₄ alkyl). Alternatively, R¹ is C₆₋₁₀ aryl or5-6 membered heteroaryl, each optionally and independently substitutedwith one or more substituents independently selected from the groupconsisting of T and C₁₋₆ aliphatic optionally substituted with one ormore instances of T; and wherein each T is halogen, cyano, Q¹, —N(R)H,—OH, —SH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H,—N(R)SO₂N(R)H, —S(O)₂Q², —N(R)Q², —OQ², —SQ², —CO₂Q², —OC(O)Q²,—C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q²,—N(R)C(O)N(R)Q², —SO₂N(R)Q², —N(R)SO₂Q², or —N(R)SO₂N(R)Q².Specifically, R¹ is phenyl optionally substituted with one or moresubstituents independently selected from the group consisting of T andC₁₋₆ aliphatic optionally substituted with one or more instances of T;and wherein each T is halogen, cyano, —N(R)H, —OH, —CO₂H, —C(O)N(R)H,—OC(O)N(R)H, —N(R)Q², —OQ², CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q²,—N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², or —N(R)C(O)N(R)Q².

i) R² is —H or C₁₋₃ alkyl; R³ is C₁₋₃ alkyl; R⁴ is —H or C₁₋₃ alkyl; andR⁵ is —H or C₁₋₃ alkyl; or ii) R² and R³ together with the atom to whichthey are bound form a C₃₋₇ cycloalkyl ring; R⁴ is —H or C₁₋₃alkyl; andR⁵ is —H or C₁₋₃alkyl.

R⁶ is —H, optionally substituted C₁₋₆ alkyl, or optionally substitutedC₃₋₇ cycloalkyl.

R⁷ is —H, or C₁₋₆ alkyl.

R⁸ is —H or C₁₋₆ alkyl.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A twenty fifth set of variables of Structural Formula (I) is as follows:

R¹ is C₁₋₄alkyl substituted with Q¹ and optionally further substitutedwith one or more substituents independently selected from the groupconsisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl),and —O(C₁-C₄ alkyl). Alternatively, R¹ is C₆₋₁₀ aryl or 5-6 memberedheteroaryl, each optionally and independently substituted with one ormore substituents independently selected from the group consisting of Tand C₁₋₆ aliphatic optionally substituted with one or more instances ofT; and wherein each T is halogen, cyano, Q¹, —N(R)H, —OH, —SH, —CO₂H,—C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H, —N(R)SO₂N(R)H,—S(O)₂Q², —N(R)Q², —OQ², —SQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q²,—N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², —N(R)C(O)N(R)Q²,—SO₂N(R)Q², —N(R)SO₂Q², or —N(R)SO₂N(R)Q². Specifically, R¹ is phenyloptionally substituted with one or more substituents independentlyselected from the group consisting of T and C₁₋₆ aliphatic optionallysubstituted with one or more instances of T; and wherein each T ishalogen, cyano, —N(R)H, —OH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H, —N(R)Q²,—OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q²,—OC(O)N(R)Q², —C(O)N(R)CO₂Q², or —N(R)C(O)N(R)Q².

i) R² is —H or C₁₋₃ alkyl; R³ is C₁₋₃alkyl; R⁴ is —H; and R⁵ is —H; orii) R² and R³ together with the atom to which they are bound form a C₃₋₇cycloalkyl ring; R⁴ is —H; and R⁵ is —H.

R⁶ is —H, optionally substituted C₁₋₆ alkyl, or optionally substitutedC₃₋₇ cycloalkyl.

R⁷ is —H, or C₁₋₆ alkyl.

R⁸ is —H or C₁₋₆ alkyl.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A twenty sixth set of variables of Structural Formula (I) is as follows:

R¹ is phenyl optionally substituted with one or more substituentsindependently selected from the group consisting of T and C₁₋₆ aliphaticoptionally substituted with one or more instances of T; and wherein eachT is halogen, cyano, —N(R)H, —OH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H,—N(R)Q², —OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q²,—OC(O)N(R)Q², —C(O)N(R)CO₂Q², or —N(R)C(O)N(R)Q².

i) R² is —H or C₁₋₃ alkyl; R³ is C₁₋₃alkyl; R⁴ is —H; and R⁵ is —H; orii) R² and R³ together with the atom to which they are bound form aC₃₋₇cycloalkyl ring; R⁴ is —H; and R⁵ is —H.

R⁶ is —H, optionally substituted C₁₋₆ alkyl, or optionally substitutedC₃₋₇ cycloalkyl.

R⁷ is —H, or C₁₋₆ alkyl.

R⁸ is —H, or C₁₋₆ alkyl.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A twenty seventh set of variables of Structural Formula (I) is asfollows:

Values, including specific values, of R¹, R², R³, R⁴, R⁵, R⁶, and R⁸ areindependently as described above in the twenty sixth set of variables ofStructural Formula (I).

R⁷ is —H.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A twenty eighth set of variables of Structural Formula (I) is asfollows:

Values, including specific values, of R¹, R², R³, R⁴, and R⁵ areindependently as described above in the twenty sixth set of variables ofStructural Formula (I).

R⁶ is optionally substituted C₃₋₆cycloalkyl

R⁷ is —H.

Values, including specific values, of the remaining variables are asdescribed above in the first set of variables of Structural Formula (I).

A twenty ninth set of variables of Structural Formula (I) is as follows:

R¹ is optionally substituted aryl or optionally substituted heteroaryl.Values, including specific values, of the remaining variables ofStructural Formula (I) are as described above in any set of the firstthrough twenty eighth sets of variables of Structural Formula (I).

A thirtieth set of variables of Structural Formula (I) is as follows:

q is 1.

Values, including specific values, of the remaining variables ofStructural Formula (I) are as described above in any set of the firstthrough twenty sixth sets of variables of Structural Formula (I).

A thirty first set of t of variables of Structural Formula (I) is asfollows:

R¹ is optionally substituted aryl or optionally substituted heteroaryl.

q is 1

Values, including specific values, of the remaining variables ofStructural Formula (I) are as described above in any set of the firstthrough twenty sixth sets of variables of Structural Formula (I).

In another embodiment, the methods of the invention can be employed inpreparing the compounds represented by Structural Formula (III) orpharmaceutically acceptable salts thereof, wherein values of thevariables of Structural Formula (III) are as described below:

In a first set of variables of Structural Formula (III), values,including specific values, of variables of Structural Formula (III) areindependently as described above in any set of the first through twentyeighth sets of variables of Structural Formula (I).

A second set of variables of Structural Formula (III) is as follows:

R⁶ is —H, C₁₋₆ aliphatic, or C₃₋₇cycloaliphatic, wherein each of theC₁₋₆ aliphatic and C₃₋₇cycloaliphatic groups is optionally andindependently substituted with one or more instances of J⁶.

Values, including specific values, of variables of Structural Formula(III) are independently as described above in the first set of variablesof Structural Formula (I).

A third set of variables of Structural Formula (III) is as follows:

R¹ is optionally substituted C₆₋₁₀ aryl or optionally substituted 5-10membered heteroaryl.

Each Z¹ is independently —N(R)—, —O—, —S—, —CO₂—, —C(O)N(R)—,—OC(O)N(R)—, —N(R)CO₂—, —N(R)C(O)N(R)—, —C(O)N(R)CO₂—, —SO₂N(R)—, or—N(R)SO₂N(R)—.

Each Z² is independently —N(R)—, —O—, —S—, —CO₂—, —OC(O)—, —C(O)N(R)—,—N(R)C(O)—, —OC(O)N(R)—, —N(R)CO₂—, —N(R)C(O)N(R)—, —C(O)N(R)CO₂—,—S(O)—, —S(O)₂—, —SO₂N(R)—, —N(R)SO₂—, or —N(R)SO₂N(R)—.

Each Q¹ is independently optionally substituted C₃₋₇cycloalkyl,optionally substituted phenyl, optionally substituted 5-6 memberedheteroaryl, or optionally substituted 4-7 membered heterocyclyl.

Each of R² and R³ is independently —H, halogen, cyano, or C₁₋₆aliphatic, or optionally R² and R³, together with the carbon atom(s) towhich they are bound, independently form a C₃₋₇cycloalkyl ring, whereineach of said aliphatic and cycloalkyl ring is independently andoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, oxo, —CN, —OH, —NH₂,—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),—CO₂H, —CO₂ (C₁-C₄ alkyl), and —O(C₁-C₄ alkyl).

R⁶ is —H, C₁₋₆ aliphatic or C₃₋₇cycloaliphatic, each of which isoptionally and independently substituted with one or more substituentsindependently selected from the group consisting of halogen, oxo, —CN,—OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl),—CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), and —O(C₁-C₄ alkyl).

Each of R⁷ and R⁸ is independently —H or C₁₋₆ alkyl.

Values, including specific values, of the remaining variables ofStructural Formula (I) are as described above in the first set ofvariables of Structural Formula (I).

In another embodiment, the methods of the invention can be employed inpreparing the compounds represented by Structural Formula (IV) orpharmaceutically acceptable salts thereof, wherein values of thevariables of Structural Formula (IV) are as described below:

In a first set of variables of Structural Formula (IV), values,including specific values, of variables of Structural Formula (IV) areindependently as described above in any set of the first through twentysixth sets of variables of Structural Formula (I).

In a second set of variables of Structural Formula (IV), values,including specific values, of variables of Structural Formula (IV) areindependently as described above in the second or third set of variablesof Structural Formula (III).

A third set of variables of Structural Formula (IV) is as follows:

Phenyl ring A is optionally substituted with one or more substitutentsindependently selected from the group consisting of T and C₁₋₆ aliphaticoptionally substituted with one or more instances of T.

Each T is halogen, cyano, Q¹, —N(R)H, —OH, —CO₂H, —C(O)N(R)H,—OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H, —N(R)SO₂N(R)H, —S(O)₂Q²,—N(R)Q², —OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q²,—OC(O)N(R)Q²-C(O)N(R)CO₂Q², —N(R)C(O)N(R)Q², —SO₂N(R)Q², —N(R)SO₂Q², or—N(R)SO₂N(R)Q².

Q¹ is C₃₋₇ cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 memberedheterocyclyl, each optionally and independently substituted with one ormore substitutents independently selected from the group consisting ofhalogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄alkyl), C₁-C₄ alkyl, C₁-C₄ haloalkyl; C₁-C₄ cyanoalkyl, C₁-C₄aminoalkyl, C₁-C₄ hydroxyalkyl, and C₂-C₄ alkoxyalkyl.

Each Q² is independently C₁₋₆ alkyl, C₃₋₇ cycloalkyl, phenyl, 5-6membered heteroaryl, or 4-7 membered heterocyclyl, or each Q², togetherwith R, optionally and independently forms an optionally substituted,4-7 membered heterocyclic ring; wherein said C₁₋₆ alkyl represented byQ² is optionally substituted with one or more substitutentsindependently selected from the group consisting of halogen, oxo, —CN,—OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl),—CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), and —O(C₁-C₄ alkyl); andwherein each of said cycloalkyl, aryl, heteroaryl, and heterocyclylgroups represented by Q² is optionally and independently substitutedwith one or more substitutents independently selected from the groupconsisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂; —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl),—O(C₁-C₄ alkyl), C₁-C₄ alkyl, C₁-C₄ haloalkyl; C₁-C₄ cyanoalkyl, C₁-C₄aminoalkyl, C₁-C₄ hydroxyalkyl, and C₂-C₄ alkoxyalkyl.

Each of R² and R³ is independently —H, halogen, optionally substitutedC₁₋₆ aliphatic; or optionally R² and R³, together with the carbon atomto which they are attached, form an optionally substitutedC₃₋₆cycloalkyl ring.

R⁶ is optionally substituted —H, optionally substituted C₁₋₆ alkyl, oroptionally substituted C₃₋₆cycloalkyl.

Each of R⁷ and R⁸ is independently —H or C₁₋₆ alkyl.

Values, including specific values, of the remaining variables ofStructural Formula (I) are as described above in the first set ofvariables of Structural Formula (I).

A fourth set of variables of Structural Formula (IV) is as follows:

Phenyl ring A is substituted with one or more substituents independentlyselected from the group consisting of —C(O)N(R)H, —C(O)N(R)Q²,—N(R)C(O)Q², —CO₂H, —CO₂Q², —OC(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², and—N(R)C(O)N(R)Q²; and optionally further substituted with one or one ormore substituents independently selected from the group consisting ofhalogen, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —O(C₁-C₄alkyl), C₁-C₄ alkyl, C₁-C₄ haloalkyl; C₁-C₄ cyanoalkyl, C₁-C₄aminoalkyl, C₁-C₄ hydroxyalkyl, and C₂-C₄ alkoxyalkyl.

Each Q² is independently C₁₋₆ alkyl, C₃₋₇cycloalkyl, phenyl, 5-6membered heteroaryl, or 4-7 membered heterocyclyl, or each Q², togetherwith R, optionally and independently forms an optionally substituted,4-7 membered heterocyclic ring; wherein said C₁₋₆ alkyl represented byQ² is optionally substituted with one or more substitutentsindependently selected from the group consisting of halogen, oxo, —CN,—OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl),—CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), and —O(C₁-C₄ alkyl); andwherein each of said cycloalkyl, aryl, heteroaryl, and heterocyclylgroups represented by Q² is optionally and independently substitutedwith one or more substitutents independently selected from the groupconsisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl),—O(C₁-C₄ alkyl), C₁-C₄ alkyl, C₁-C₄ haloalkyl; C₁-C₄ cyanoalkyl, C₁-C₄aminoalkyl, C₁-C₄ hydroxyalkyl, and C₂-C₄ alkoxyalkyl.

Each of R² and R³ is independently —H, halogen, optionally substitutedC₁₋₆ aliphatic; or optionally R² and R³, together with the carbon atomto which they are attached, form an optionally substitutedC₃₋₆cycloalkyl ring.

R⁶ is optionally substituted —H, optionally substituted C₁₋₆ alkyl, oroptionally substituted C₃₋₆ cycloalkyl.

Each of R⁷ and R⁸ is independently —H or C₁₋₆ alkyl.

Values, including specific values, of the remaining variables ofStructural Formula (I) are as described above in the first set ofvariables of Structural Formula (I).

A fifth set of variables of Structural Formula (IV) is as follows:

Phenyl ring A is substituted with —OC(O)Q², —C(O)N(R)Q², or —N(R)C(O)Q²,and optionally further substituted with one or one or more substituentsindependently selected from the group consisting of halogen, —CN, —OH,—NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —O(C₁-C₄ alkyl), C₁-C₄ alkyl,C₁-C₄ haloalkyl; C₁-C₄ cyanoalkyl, C₁-C₄ aminoalkyl, C₁-C₄ hydroxyalkyl,and C₂-C₄ alkoxyalkyl.

Each Q² is independently C₁₋₆ alkyl, C₃₋₇cycloalkyl, phenyl, 5-6membered heteroaryl, or 4-7 membered heterocyclyl, or each Q², togetherwith R, optionally and independently forms an optionally substituted,4-7 membered heterocyclic ring; wherein said C₁₋₆ alkyl represented byQ² is optionally substituted with one or more substitutentsindependently selected from the group consisting of halogen, oxo, —CN,—OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl),—CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), and —O(C₁-C₄ alkyl); andwherein each of said cycloalkyl, aryl, heteroaryl, and heterocyclylgroups represented by Q² is optionally and independently-substitutedwith one or more substitutents independently selected from the groupconsisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl),—O(C₁-C₄ alkyl), C₁-C₄ alkyl, C₁-C₄ haloalkyl; C₁-C₄ cyanoalkyl, C₁-C₄aminoalkyl, C₁-C₄ hydroxyalkyl, and C₂-C₄ alkoxyalkyl.

Each of R² and R³ is independently —H, halogen, optionally substitutedC₁₋₆ aliphatic; or optionally R² and R³, together with the carbon atomto which they are attached, form an optionally substituted C₃₋₆cycloalkyl ring.

R⁶ is optionally substituted —H, optionally substituted C₁₋₆ alkyl, oroptionally substituted C₃₋₆cycloalkyl.

Each of R⁷ and R⁸ is independently —H or C₁₋₆ alkyl.

Values, including specific values, of the remaining variables ofStructural Formula (I) are as described above in the first set ofvariables of Structural Formula (I).

A sixth set of variables of Structural Formula (IV) is as follows:

R⁶ is C₅₋₆ cycloalkyl.

Values, including specific values, of the remaining variables ofStructural Formula (IV) are independently as described in the second,third or fourth set of variables of Structural Formula (IV).

A seventh set of variables of Structural Formula (IV) is as follows:

R² is —H or C₁₋₃alkyl, and R³ is C₁₋₃alkyl; or R² and R³ together withthe atom to which they are bound form a C₃₋₆cycloalkyl ring.

R⁶ is C₅₋₆cycloalkyl.

Values, including specific values, of the remaining variables ofStructural Formula (IV) are independently as described in the second,third or fourth set of variables of Structural Formula (IV).

In yet another embodiment, the methods of the invention can be employedin preparing the compounds represented by any one of the followingstructural formulae, or pharmaceutically acceptable salts thereof:

In yet another embodiment, the methods of the invention can be employedin preparing the compounds represented by any one of the followingstructural formulae, or pharmaceutically acceptable salts thereof:

In yet another embodiment, the methods of the invention can be employedin preparing the compounds represented by any one of the followingstructural formulae, or pharmaceutically acceptable salts thereof:

In yet another embodiment, the methods of the invention can be employedin preparing the compound represented by the following structuralformula, or a pharmaceutically acceptable salt thereof:

In yet another embodiment, the methods of the invention can be employedin preparing the compound represented by the following structuralformula, or a pharmaceutically acceptable salt thereof:

Additional examples of compounds that can be prepared by the methods ofthe invention can be found in, for example, US 2008/0167289, US2008/0009492, US 2006/004014, U.S. Pat. No. 6,806,272, U.S. Pat. No.6,861,422, WO2009/040556, WO 2009/042711, and WO 2006/058876.

In some embodiments, the methods of the invention further comprise thestep of reacting a compound of Structural Formula (C):

with a compound of Structural Formula (D):

under suitable conditions to form the compound represented by StructuralFormula (A). LG₃ is a suitable leaving group, such as a halogen.Specifically, LG₃ is —Cl. Details of this reaction are as describedabove.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds described above may involve, at various stages, the additionand removal of one or more protecting groups. The protection anddeprotection of functional groups is described in “Protective Groups inOrganic Chemistry.” edited by J. W. F. McOmie, Plenum Press (1973) and“Protective Groups in Organic Synthesis,” 3rd edition, T. W. Greene andP. G. M. Wuts, Wiley Interscience, and “Protecting Groups,” 3rd edition,P. J. Kocienski, Thieme (2005)

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausolito: 1999, and “March'sAdvanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as illustrated generallybelow, or as exemplified by particular classes, subclasses, and speciesof the compounds described above. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of one or more hydrogen radicals in a given structure withthe radical of a specified substituent. Unless otherwise indicated, anoptionally substituted group may have a substituent at eachsubstitutable position of the group. When more than one position in agiven structure can be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at each position. When the term “optionally substituted”precedes a list, said term refers to all of the subsequent substitutablegroups in that list. If a substituent radical or structure is notidentified or defined as “optionally substituted”, the substituentradical or structure is unsubstituted. For example, if X is optionallysubstituted C₁-C₃ alkyl or phenyl; X may be either optionallysubstituted C₁-C₃ alkyl or optionally substituted phenyl. Likewise, ifthe term “optionally substituted” follows a list, said term also refersto all of the substitutable groups in the prior list unless otherwiseindicated. For example: if X is C₁-C₃ alkyl or phenyl wherein X isoptionally and independently substituted by J^(X), then both C₁-C₃ alkyland phenyl may be optionally substituted by J^(X). As is apparent to onehaving ordinary skill in the art, groups such as H, halogen, NO₂, CN,NH₂, OH, or OCF₃ would not be substitutable groups.

The phrase “up to”, as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 3” means any one of 0, 1, 2, and 3. As described herein, aspecified number range of atoms includes any integer therein. Forexample, a group having from 1-4 atoms could have 1, 2, 3, or 4 atoms.

Selection of substituents and combinations of substituents envisioned bythis invention are those that result in the formation of stable orchemically feasible compounds. The term “stable”, as used herein, refersto compounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, specifically,their recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week. Only those choicesand combinations of substituents that result in a stable structure arecontemplated. Such choices and combinations will be apparent to those ofordinary skill in the art and may be determined without undueexperimentation.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched), or branched, hydrocarbon chain thatis completely saturated or that contains one or more units ofunsaturation but is non-aromatic. Unless otherwise specified, aliphaticgroups contain 1-10 aliphatic carbon atoms. In some embodiments,aliphatic groups contain 1-6 aliphatic carbon atoms. In otherembodiments, aliphatic groups contain 1-4 aliphatic carbon atoms.Aliphatic groups may be linear or branched, substituted or unsubstitutedalkyl, alkenyl, or alkynyl groups. Specific examples include, but arenot limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl,n-butenyl, ethynyl, and tert-butyl and acetylene.

The term “alkyl” as used herein means a saturated straight or branchedchain hydrocarbon. The term “alkenyl” as used herein means a straight orbranched chain hydrocarbon comprising one or more double bonds. The term“alkynyl” as used herein means a straight or branched chain hydrocarboncomprising one or more triple bonds. Each of the “alkyl”, “alkenyl” or“alkynyl” as used herein can be optionally substituted as set forthbelow. In some embodiments, the “alkyl” is C₁-C₆ alkyl or C₁-C₄ alkyl.In some embodiments, the “alkenyl” is C₂-C₆ alkenyl or C₂-C₄ alkenyl. Insome embodiments, the “alkynyl” is C₂-C₆ alkynyl or C₂-C₄ alkynyl.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl” or“carbocyclic”) refers to a non-aromatic carbon only containing ringsystem which can be saturated or contains one or more units ofunsaturation, having three to fourteen ring carbon atoms. In someembodiments, the number of carbon atoms is 3 to 10. In otherembodiments, the number of carbon atoms is 4 to 7. In yet otherembodiments, the number of carbon atoms is 5 or 6. The term includesmonocyclic, bicyclic or polycyclic, fused, spiro or bridged carbocyclicring systems. The term also includes polycyclic ring systems in whichthe carbocyclic ring can be “fused” to one or more non-aromaticcarbocyclic or heterocyclic rings or one or more aromatic rings orcombination thereof, wherein the radical or point of attachment is onthe carbocyclic ring. “Fused” bicyclic ring systems comprise two ringswhich share two adjoining ring atoms. Bridged bicyclic group comprisetwo rings which share three or four adjacent ring atoms. Spiro bicyclicring systems share one ring atom. Examples of cycloaliphatic groupsinclude, but are not limited to, cycloalkyl and cycloalkenyl groups.Specific examples include, but are not limited to, cyclohexyl,cyclopropenyl, and cyclobutyl.

The term “heterocycle” (or “heterocyclyl,” or “heterocyclic” or“non-aromatic heterocycle”) as used herein refers to a non-aromatic ringsystem which can be saturated or contain one or more units ofunsaturation, having three to fourteen ring atoms in which one or morering carbons is replaced by a heteroatom such as, N, S, or O and eachring in the system contains 3 to 7 members. In some embodiments,non-aromatic heterocyclic rings comprise up to three heteroatomsselected from N, S and O within the ring. In other embodiments,non-aromatic heterocyclic rings comprise up to two heteroatoms selectedfrom N, S and O within the ring system. In yet other embodiments,non-aromatic heterocyclic rings comprise up to two heteroatoms selectedfrom N and O within the ring system. The term includes monocyclic,bicyclic or polycyclic fused, spiro or bridged heterocyclic ringsystems. The term also includes polycyclic ring systems in which theheterocyclic ring can be fused to one or more non-aromatic carbocyclicor heterocyclic rings or one or more aromatic rings or combinationthereof, wherein the radical or point of attachment is on theheterocyclic ring. Examples of heterocycles include, but are not limitedto, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl,triazocanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl,benzimidazolonyl, tetrahydrofuranyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydrothiophenyl, morpholino, including, forexample, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino,4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolanyl,benzodithianyl, 3-(1-alkyl)-benzimidazol-2-onyl, and1,3-dihydro-imidazol-2-onyl.

The term “aryl” (or “aryl ring” or “aryl group”) used alone or as partof a larger moiety as in “aralkyl”, “aralkoxy”, “aryloxyalkyl”, or“heteroaryl” refers to carbocyclic aromatic ring systems. The term“aryl” may be used interchangeably with the terms “aryl ring” or “arylgroup”. “Carbocyclic aromatic ring” groups have only carbon ring atoms(typically six to fourteen) and include monocyclic aromatic rings suchas phenyl and fused polycyclic aromatic ring systems in which two ormore carbocyclic aromatic rings are fused to one another. Examplesinclude 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Alsoincluded within the scope of the term “carbocyclic aromatic ring” or“carbocyclic aromatic”, as it is used herein, is a group in which anaromatic ring is “fused” to one or more non-aromatic rings (carbocyclicor heterocyclic), such as in an indanyl, phthalimidyl, naphthimidyl,phenanthridinyl, or tetrahydronaphthyl, where the radical or point ofattachment is on the aromatic ring.

The terms “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroarylgroup”, “aromatic heterocycle” or “heteroaromatic group”, used alone oras part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”,refer to heteroaromatic ring groups having five to fourteen members, inwhich one or more ring carbons is replaced by a heteroatom such as, N,S, or O. In some embodiments, heteroaryl rings comprise up to threeheteroatoms selected from N, S and O within the ring. In otherembodiments, heteroaryl rings comprise up to two heteroatoms selectedfrom N, S and O within the ring system. In yet other embodiments,heteroaryl rings comprise up to two heteroatoms selected from N and Owithin the ring system. Heteroaryl rings include monocyclicheteroaromatic rings and polycyclic aromatic rings in which a monocyclicaromatic ring is fused to one or more other aromatic rings. Alsoincluded within the scope of the term “heteroaryl”, as it is usedherein, is a group in which an aromatic ring is “fused” to one or morenon-aromatic rings (carbocyclic or heterocyclic), where the radical orpoint of attachment is on the aromatic ring. Bicyclic 6,5 heteroaromaticring, as used herein, for example, is a six membered heteroaromatic ringfused to a second five membered ring, wherein the radical or point ofattachment is on the six membered ring. Examples of heteroaryl groupsinclude pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl,pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl including, forexample, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl,5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl,4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl,tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl,benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl,benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl,acridinyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl,pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

As used herein, “cyclo”, “cyclic”, “cyclic group” or “cyclic moiety”,include mono-, bi-, and tri-cyclic ring systems includingcycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of whichhas been previously defined.

As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or11) membered structures that form two rings, wherein the two rings haveat least one atom in common (e.g., 2 atoms in common). Bicyclic ringsystems include bicycloaliphatics (e.g., bicycloalkyl orbicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclicheteroaryls.

As used herein, a “bridged bicyclic ring system” refers to a bicyclicheterocycloalipahtic ring system or bicyclic cycloaliphatic ring systemin which the rings are bridged. Examples of bridged bicyclic ringsystems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system canbe optionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, “bridge” refers to a bond or an atom or an unbranchedchain of atoms connecting two different parts of a molecule. The twoatoms that are connected through the bridge (usually but not always, twotertiary carbon atoms) are denotated as “bridgeheads”.

As used herein, the term “spiro” refers to ring systems having one atom(usually a quaternary carbon) as the only common atom between two rings.

The term “ring atom” is an atom such as C, N, O or S that is in the ringof an aromatic group, cycloalkyl group or non-aromatic heterocyclicring.

A “substitutable ring atom” in an aromatic group is a ring carbon ornitrogen atom bonded to a hydrogen atom. The hydrogen can be optionallyreplaced with a suitable substituent group. Thus, the term“substitutable ring atom” does not include ring nitrogen or carbon atomswhich are shared when two rings are fused. In addition, “substitutablering atom” does not include ring carbon or nitrogen atoms when thestructure depicts that they are already attached to a moiety other thanhydrogen.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

As used herein an optionally substituted aralkyl can be substituted onboth the alkyl and the aryl portion. Unless otherwise indicated as usedherein optionally substituted aralkyl is optionally substituted on thearyl portion.

In some embodiments, an aliphatic group and a heterocyclic ring mayindependently contain one or more substituents. Suitable substituents onthe saturated carbon of an aliphatic group or of a non-aromaticheterocyclic ring are selected from those described above, for example,in the definition of J^(A) and J^(B). Other suitable substitutentsinclude those listed as suitable for the unsaturated carbon of an arylor heteroaryl group and additionally include the following: ═O, ═S,═NNHR*, ═NN(R*)₂, ═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*,wherein each R* is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic. Optional substituents on the aliphatic groupof R* are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂,halogen, C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic), whereineach of the foregoing C₁₋₄ aliphatic groups of R* is unsubstituted.

In some embodiments, optional substituents on the nitrogen of aheterocyclic ring include those described above. Examples of suchsuitable substituents include —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)₂, —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄ alkyl),and C₁-C₄ aliphatic that is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄alkyl), C₃₋₇cycloalkyl, and C₃₋₇cyclo(haloalkyl). Other suitablesubstituents include —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or—NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C₁₋₆aliphatic, optionally substituted phenyl, optionally substituted —O(Ph),optionally substituted —CH₂ (Ph), optionally substituted —(CH₂)₂(Ph);optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 memberedheteroaryl or heterocyclic ring having one to four heteroatomsindependently selected from oxygen, nitrogen, or sulfur, or, twoindependent occurrences of R⁺, on the same substituent or differentsubstituents, taken together with the atom(s) to which each R⁺ group isbound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclylring has 1-3 heteroatoms independently selected from nitrogen, oxygen,or sulfur. Optional substituents on the aliphatic group or the phenylring of R⁺ are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN,CO₂H, CO₂ (C₁₋₄ aliphatic), O(halo C₁₋₄ aliphatic), or halo(C₁₋₄aliphatic), wherein each of the foregoing C₁₋₄ aliphatic groups of R⁺ isunsubstituted.

In some embodiments, an aryl (including aralkyl, aralkoxy, aryloxyalkyland the like) or heteroaryl (including heteroaralkyl andheteroarylalkoxy and the like) group may contain one or moresubstituents. Suitable substituents on the unsaturated carbon atom of anaryl or heteroaryl group are selected from those described above.Specific examples include halogen, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), —O(C₁-C₄ alkyl), and C₁-C₄ aliphatic that is optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), —O(C₁-C₄ alkyl), C₃₋₇ cycloalkyl, andC₃₋₇cyclo(haloalkyl). Other suitable substituents include: halogen;—R^(o); —OR^(o); —SR^(o); 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl(Ph) optionally substituted with Ro; —O(Ph) optionally substituted withR^(o); —(CH₂)₁₋₂(Ph), optionally substituted with R^(o); —CH═CH(Ph),optionally substituted with R^(o); —NO₂; —CN; —N(R^(o))₂;—NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂;—NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o);—NR^(o)NR^(o)C(O)N(R^(o))₂; —NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o);—C(O)CH₂C(O)R^(o); —CO₂R^(o); —C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂;—C(S)N(R^(o))₂; —OC(O)N(R^(o))₂; —OC(O)R^(o); —C(O)N(OR^(o))R^(o);—C(NOR^(o))R^(o); —S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o);—NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —N(OR^(o))R^(o);—C(═NH)—N(R^(o))₂; or —(CH₂)₀₋₂NHC(O)R^(o); wherein each independentoccurrence of R^(o) is selected from hydrogen, optionally substitutedC₁₋₆ aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclicring, phenyl, —O(Ph), or —CH₂ (Ph), or, two independent occurrences ofR^(o), on the same substituent or different substituents, taken togetherwith the atom(s) to which each R^(o) group is bound, form a 5-8-memberedheterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkylring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Optionalsubstituents on the aliphatic group of R^(o) are selected from NH₂,NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, OH,O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂ (C₁₋₄ aliphatic), O(haloC₁₋₄aliphatic), or haloC₁₋₄ aliphatic, CHO, N(CO)(C₁₋₄ aliphatic),C(O)N(C₁₋₄ aliphatic), wherein each of the foregoing C₁₋₄ aliphaticgroups of R^(o) is unsubstituted.

Non-aromatic nitrogen containing heterocyclic rings that are substitutedon a ring nitrogen and attached to the remainder of the molecule at aring carbon atom are said to be N substituted. For example, an N alkylpiperidinyl group is attached to the remainder of the molecule at thetwo, three or four position of the piperidinyl ring and substituted atthe ring nitrogen with an alkyl group. Non-aromatic nitrogen containingheterocyclic rings such as pyrazinyl that are substituted on a ringnitrogen and attached to the remainder of the molecule at a second ringnitrogen atom are said to be N′ substituted-N-heterocycles. For example,an N′ acyl N-pyrazinyl group is attached to the remainder of themolecule at one ring nitrogen atom and substituted at the second ringnitrogen atom with an acyl group.

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined herein), may betaken together with the atom(s) to which each variable is bound to forma 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3-8-memberedcycloalkyl ring. Exemplary rings that are formed when two independentoccurrences of R^(o) (or R⁺, or any other variable similarly definedherein) are taken together with the atom(s) to which each variable isbound include, but are not limited to the following: a) two independentoccurrences of R^(o) (or R⁺, or any other variable similarly definedherein) that are bound to the same atom and are taken together with thatatom to form a ring, for example, N(R^(o))₂, where both occurrences ofR^(o) are taken together with the nitrogen atom to form apiperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) twoindependent occurrences of R^(o) (or R⁺, or any other variable similarlydefined herein) that are bound to different atoms and are taken togetherwith both of those atoms to form a ring, for example where a phenylgroup is substituted with two occurrences of

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(o) (or R⁺, or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

As used herein, an “amino” group refers to —NH₂.

The term “hydroxyl” or “hydroxy” or “alcohol moiety” refers to —OH.

As used herein, an “oxo” refers to ═O.

As used herein, the term “alkoxy”, or “alkylthio”, as used herein,refers to an alkyl group, as previously defined, attached to themolecule through an oxygen (“alkoxy” e.g., —O-alkyl) or sulfur(“alkylthio” e.g., —S-alkyl) atom.

As used herein, the terms “halogen”, “halo”, and “hal” mean F, Cl, Br,or I.

As used herein, the term “cyano” or “nitrile” refer to —CN or —C≡N.

The terms “alkoxyalkyl”, “alkoxyalkenyl”, “alkoxyaliphatic”, and“alkoxyalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more alkoxy groups.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be,substituted with one or more halogen atoms. This term includesperfluorinated alkyl groups, such as —CF₃ and —CF₂CF₃.

The terms “cyanoalkyl”, “cyanoalkenyl”, “cyanoaliphatic”, and“cyanoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more cyano groups. In some embodiments, thecyanoalkyl is (NC)-alkyl-.

The terms “aminoalkyl”, “aminoalkenyl”, “aminoaliphatic”, and“aminoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more amino groups, wherein the amino groupis as defined above.

The terms “hydroxyalkyl”, “hydroxyaliphatic”, and “hydroxyalkoxy” meanalkyl, aliphatic or alkoxy, as the case may be, substituted with one ormore —OH groups.

The terms “alkoxyalkyl”, “alkoxyaliphatic”, and “alkoxyalkoxy” meanalkyl, aliphatic or alkoxy, as the case may be, substituted with one ormore alkoxy groups. For example, an “alkoxyalkyl” refers to an alkylgroup such as (alkyl-O)-alkyl-, wherein alkyl has been defined above.

The term “protecting group” and “protective group” as used herein, areinterchangeable and refer to an agent used to temporarily block one ormore desired functional groups in a compound with multiple reactivesites. In certain embodiments, a protecting group has one or more, orspecifically all, of the following characteristics: a) is addedselectively to a functional group in good yield to give a protectedsubstrate that is b) stable to reactions occurring at one or more of theother reactive, sites; and c) is selectively removable in good yield byreagents that do not attack the regenerated, deprotected functionalgroup. As would be understood by one skilled in the art, in some cases,the reagents do not attack other reactive groups in the compound. Inother cases, the reagents may also react with other reactive groups inthe compound. Examples of protecting groups are detailed in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, ThirdEdition, John Wiley & Sons, New York: 1999 (and other editions of thebook), the entire contents of which are hereby incorporated byreference. The term “nitrogen protecting group”, as used herein, refersto an agent used to temporarily block one or more desired nitrogenreactive sites in a multifunctional compound. Preferred nitrogenprotecting groups also possess the characteristics exemplified for aprotecting group above, and certain exemplary nitrogen protecting groupsare also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in“Protective Groups in Organic Synthesis”, Third Edition, John Wiley &Sons, New York: 1999, the entire contents of which are herebyincorporated by reference.

As used herein, the term “displaceable moiety” or “leaving group” refersto a group that is associated with an aliphatic or aromatic group asdefined herein and is subject to being displaced by nucleophilic attackby a nucleophile.

Unless otherwise indicated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, cis-trans,conformational, and rotational) forms of the structure. For example, theR and S configurations for each asymmetric center, (Z) and (E) doublebond isomers, and (Z) and (E) conformational isomers are included inthis invention, unless only one of the isomers is drawn specifically. Aswould be understood to one skilled in the art, a substituent can freelyrotate around any rotatable bonds. For example, a substituent drawn as

also represents

Therefore, single stereochemical isomers as well as enantiomeric,diastereomeric, cis/trans, conformational, and rotational mixtures ofthe present compounds are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Additionally, unless otherwise indicated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.Such compounds, especially deuterium analogs, can also betherapeutically useful.

The terms “a bond” and “absent” are used interchangeably to indicatethat a group is absent.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

The compounds described herein can exist in free form, or, whereappropriate, as salts. Those salts that are pharmaceutically acceptableare of particular interest since they are useful in administering thecompounds described above for medical purposes. Salts that are notpharmaceutically acceptable are useful in manufacturing processes, forisolation and purification purposes, and in some instances, for use inseparating stereoisomeric forms of the compounds of the invention orintermediates thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts of a compound, which are, within the scope of sound medicaljudgment, suitable for use in humans and lower animals without undueside effects, such as, toxicity, irritation, allergic response and thelike, and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsdescribed herein include those derived from suitable inorganic andorganic acids and bases. These salts can be prepared in situ during thefinal isolation and purification of the compounds.

Where the compound described herein contains a basic group, or asufficiently basic bioisostere, acid addition salts can be preparedby 1) reacting the purified compound in its free-base form with asuitable organic or inorganic acid and 2) isolating the salt thusformed. In practice, acid addition salts might be a more convenient formfor use and use of the salt amounts to use of the free basic form.

Examples of pharmaceutically acceptable, non-toxic acid addition saltsare salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like.

Where the compound described herein contains a carboxy group or asufficiently acidic bioisostere, base addition salts can be preparedby 1) reacting the purified compound in its acid form with a suitableorganic or inorganic base and 2) isolating the salt thus formed. Inpractice, use of the base addition salt might be more convenient and useof the salt form inherently amounts to use of the free acid form. Saltsderived from appropriate bases include alkali metal (e.g., sodium,lithium, and potassium), alkaline earth metal (e.g., magnesium andcalcium), ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention alsoenvisions the quaternization of any basic nitrogen-containing groups ofthe compounds disclosed herein. Water or oil-soluble or dispersibleproducts may be obtained by such quaternization.

Basic addition salts include pharmaceutically acceptable metal and aminesalts. Suitable metal salts include the sodium, potassium, calcium,barium, zinc, magnesium, and aluminium. The sodium and potassium saltsare usually preferred. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Suitable inorganic base addition salts are prepared frommetal bases which include sodium hydride, sodium hydroxide, potassiumhydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide,magnesium hydroxide, zinc hydroxide and the like. Suitable amine baseaddition salts are prepared from amines which are frequently used inmedicinal chemistry because of their low toxicity and acceptability formedical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, dietanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine,dehydroabietylamine, N-ethylpiperidine, benzylamine,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and thelike.

Other acids and bases, while not in themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds described herein and theirpharmaceutically acceptable acid or base addition salts.

It should be understood that this invention includesmixtures/combinations of different pharmaceutically acceptable salts andalso mixtures/combinations of compounds in free form andpharmaceutically acceptable salts.

In addition to the compounds described herein, the methods of theinvention can be employed for preparing pharmaceutically acceptablesolvates (e.g., hydrates) and clathrates of these compounds.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more pharmaceuticallyacceptable solvent molecules to one of the compounds described herein.The term solvate includes hydrates (e.g., hemihydrate, monohydrate,dihydrate, trihydrate, tetrahydrate, and the like).

As used herein, the term “hydrate” means a compound described herein ora salt thereof that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

As used herein, he term “clathrate” means a compound described herein ora salt thereof in the form of a crystal lattice that contains spaces(e.g., channels) that have a guest molecule e.g., a solvent or water)trapped within.

In addition to the compounds described herein, the methods of theinvention can be employed for preparing pharmaceutically acceptablederivatives or prodrugs of these compounds.

A “pharmaceutically acceptable derivative or prodrug” includes anypharmaceutically acceptable ester, salt of an ester, or other derivativeor salt thereof, of a compound described herein, which, uponadministration to a recipient, is capable of providing, either directlyor indirectly, a compound described herein or an inhibitorily activemetabolite or residue thereof. Particularly favoured derivatives orprodrugs are those that increase the bioavailability of the compoundswhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound described herein. Prodrugs may become active upon such reactionunder biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated in this inventioninclude, but are not limited to, analogs or derivatives of compounds ofthe invention that comprise biohydrolyzable moieties such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. Other examples of prodrugs includederivatives of compounds described herein that comprise —NO, —NO₂, —ONO,or —ONO₂ moieties. Prodrugs can typically be prepared using well-knownmethods, such as those described by BURGER'S MEDICINAL CHEMISTRY ANDDRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).

A “pharmaceutically acceptable derivative” is an adduct or derivativewhich, upon administration to a patient in need, is capable ofproviding, directly or indirectly, a compound as otherwise describedherein, or a metabolite or residue thereof. Examples of pharmaceuticallyacceptable derivatives include, but are not limited to, esters and saltsof such esters.

Pharmaceutically acceptable prodrugs of the compounds described aboveinclude, without limitation, esters, amino acid esters, phosphateesters, metal salts and sulfonate esters.

The compounds described above are useful as protein kinase inhibitors,such as Plk (Plk1, Plk2, Plk3, and/or Plk4) inhibitors. Thus, thesecompounds can inhibit the activity of such protein kinase(s) in apatient. Generally, inhibiting such protein kinase activity can treat orprevent a condition selected from autoimmune diseases, inflammatorydiseases, proliferative and hyperproliferative diseases,immunologically-mediated diseases, bone diseases, metabolic diseases,neurological and neurodegenerative diseases, cardiovascular diseases,hormone related diseases, allergies, asthma, and Alzheimer's disease.

Particularly, the compounds described above are useful for the treatmentof diseases, disorders, and conditions characterized by excessive orabonormal cell proliferation. Such diseases include a proliferative orhyperproliferative disease, and a neurodegenerative disease. Examples ofproliferative and hyperproliferative diseases include, withoutlimitation, cancer.

The term “cancer” includes, but is not limited to, the followingcancers: breast; ovary; cervix; prostate; testis, genitourinary tract;esophagus; larynx, glioblastoma; neuroblastoma; stomach; skin,keratoacanthoma; lung, epidermoid carcinoma, large cell carcinoma, smallcell carcinoma, lung adenocarcinoma; bone; colon; colorectal; adenoma;pancreas, adenocarcinoma; thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma; seminoma; melanoma;sarcoma; bladder carcinoma; liver carcinoma and biliary passages; kidneycarcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairycells; buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx;small intestine; colon-rectum, large intestine, rectum; brain andcentral nervous system; chronic myeloid leukemia (CML), and leukemia.The term “cancer” includes, but is not limited to, the followingcancers: myeloma, lymphoma, or a cancer selected from gastric, renal, orand the following cancers: head and neck, oropharangeal, non-small celllung cancer (NSCLC), endometrial, hepatocarcinoma, Non-Hodgkinslymphoma, and pulmonary.

The term “cancer” also includes, but is not limited to, the followingcancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx;Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung:bronchogenic carcinoma (squamous cell or epidermoid, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel or small intestines (adenocarcinoma,lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel or large intestines(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), colon, colon-rectum, colorectal; rectum, Genitourinarytract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma,leukemia), bladder and urethra (squamous cell carcinoma, transitionalcell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma),testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myiloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma [malignant lymphoma]hairy cell; lymphoiddisorders; Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi,lipoma, angioma, dermatofibroma, keloids, psoriasis, Thyroid gland:papillary thyroid carcinoma, follicular thyroid carcinoma; medullarythyroid carcinoma, undifferentiated thyroid cancer, multiple endocrineneoplasia type 2A, multiple endocrine neoplasia type 2B, familialmedullary thyroid cancer, pheochromocytoma, paraganglioma; and Adrenalglands: neuroblastoma. Thus, the term “cancerous cell” as providedherein, includes a cell afflicted by any one of the above-identifiedconditions.

More particularly, the compounds described above are useful for treatingcancer, such as colorectal, thyroid, breast, and lung cancer; andmyeloproliferative disorders, such as polycythemia vera,thrombocythemia, myeloid metaplasia with myelofibrosis, chronicmyelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilicsyndrome, juvenile myelomonocytic leukemia, and systemic mast celldisease. Specific examples of diseases and conditions where thecompounds described herein and their compositions are useful includehematopoietic disorders, in particular, acute-myelogenous leukemia(AML), chronic-myelogenous leukemia (CML), acute-promyelocytic leukemia(APL), and acute lymphocytic leukemia (ALL). Examples ofneurodegenerative diseases include, without limitation, Alzheimer'sdisease.

The compounds described above can be particularly useful for treating aprotein-kinase mediated condition, such as a Plk-mediated disease. Theterm “protein kinase-mediated condition,” as used herein, means anydisease or other deleterious condition in which a protein kinase plays arole. Such conditions include, without limitation, autoimmune diseases,inflammatory diseases, proliferative and hyperproliferative diseases,immunologically-mediated diseases, bone diseases, metabolic diseases,neurological and neurodegenerative diseases, cardiovascular diseases,hormone related diseases, allergies, asthma, and Alzheimer's disease.The term “Plk-mediated condition”, as used herein means any disease orother deleterious condition in which Plk plays a role. Such conditionsinclude, without limitation, a proliferative or hyperproliferativedisease, or a neurodegenerative disease.

As used herein, a “patient” means an animal, preferably a human.

An “effective amount” of a compound for treating or preventing a proteinkinase-mediated disease/condition (e.g., a Plk-mediateddisease/condition) is the amount effective in order to treat saiddisease/condition. The compounds described above may be administeredusing any amount and any route of administration effective for treatingor lessening the severity of said disease. For example, the compoundscan be administered in a dosage of between 0.01-100 mg/kg bodyweight/day.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of the compound will also depend upon the particular compound inthe composition.

Depending upon the particular protein kinase-mediated conditions to betreated or prevented, additional drugs, which are normally administeredto treat or prevent that condition, may be administered together withthe protease inhibitors described herein. For example, chemotherapeuticagents or other anti-proliferative agents may be combined with theprotein kinase inhibitors of this invention to treat proliferativediseases.

Those additional agents may be administered separately, as part of amultiple dosage regimen, from the protein kinase inhibitor-containingcompound or composition. Alternatively, those agents may be part of asingle dosage form, mixed together with the protein kinase inhibitor ina single composition.

Examples of known chemotherapeutic agents include, but are not limitedto, Gleevec™, adriamycin, dexamethasone, vincristine, cyclophosphamide,fluorouracil, topotecan, taxol, interferons, and platinum derivatives.Other examples of agents the inhibitors of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for Parkinson'sDisease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole,bromocriptine, pergolide, trihexephendyl, and amantadine; agents fortreating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such asalbuterol and Singulair®; agents for treating schizophrenia such aszyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agentssuch as corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

As inhibitors of protein kinases, the compounds described above are alsouseful in biological samples. For example, the compounds are useful ininhibiting protein kinase activity in a biological sample. The term“biological sample”, as used herein, means an in vitro or an ex vivosample, including, without limitation, cell cultures or extractsthereof; biopsied material obtained from a mammal or extracts thereof;and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof.

Inhibition of protein kinase activity in a biological sample is usefulfor a variety of purposes that are known to one of skill in the art.Examples of such purposes include, but are not limited to, bloodtransfusion, organ-transplantation, and biological specimen storage.

The compounds described above are also useful the study of proteinkinases in biological and pathological phenomena; the study ofintracellular signal transduction pathways mediated by such proteinkinases; and the comparative evaluation of new protein kinaseinhibitors. Examples of such uses include, but are not limited to,biological assays such as enzyme assays and cell-based assays.

The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the kinase activity or ATPaseactivity of the activated kinase. Alternate in vitro assays quantitatethe ability of the inhibitor to bind to the protein kinase and may bemeasured either by radiolabelling the inhibitor prior to binding,isolating the inhibitor/kinase complex and determining the amount ofradiolabel bound, or by running a competition experiment where newinhibitors are incubated with the kinase bound to known radioligands.Protein kinase inhibition assays are known in the art. For example,detailed conditions for Plk1, Plk2, Plk3, and Plk4 are set forth in US2008/0167289 and US 2009/0062292.

In treating or preventing one or more conditions/diseases describedabove, the compounds described above can be formulated inpharmaceutically acceptable formulations that optionally furthercomprise a pharmaceutically acceptable carrier, adjuvant or vehicle.

As described herein, the pharmaceutically acceptable compositionscomprise a compound described above in an effective amount, andadditionally comprise a pharmaceutically acceptable carrier, adjuvant,or vehicle, which includes any and all solvents, diluents, or otherliquid vehicle, dispersion or suspension aids, surface active agents,isotonic agents, thickening or emulsifying agents, preservatives, solidbinders, lubricants and the like, as suited to the particular dosageform desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. As used herein,the phrase “side effects” encompasses unwanted and adverse effects of atherapy (e.g., a prophylactic or therapeutic agent). Side effects arealways unwanted, but unwanted effects are not necessarily adverse. Anadverse effect from a therapy (e.g., prophylactic or therapeutic agent)might be harmful or uncomfortable or risky.

A pharmaceutically acceptable carrier may contain inert ingredientswhich do not unduly inhibit the biological activity of the compounds.The pharmaceutically acceptable carriers should be biocompatible, e.g.,non-toxic, non-inflammatory, non-immunogenic or devoid of otherundesired reactions or side-effects upon the administration to asubject. Standard pharmaceutical formulation techniques can be employed.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins (such as humanserum albumin), buffer substances (such as twin 80, phosphates, glycine,sorbic acid, or potassium sorbate), partial glyceride mixtures ofsaturated vegetable fatty acids, water, salts or electrolytes (such asprotamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, or zinc salts), colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, methylcellulose,hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucoseand sucrose; starches such as corn starch and potato starch; celluloseand its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients such as cocoa butter and suppository waxes; oils suchas peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil;corn oil and soybean oil; glycols; such a propylene glycol orpolyethylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The compounds described above, and pharmaceutically acceptablecompositions thereof can be administered to humans and other animalsorally, rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments, or drops),bucally, as an oral or nasal spray, or the like, depending on theseverity of the infection being treated. The term “parenteral” as usedherein includes, but is not limited to, subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. Specifically, the compositions are administeredorally, intraperitoneally or intravenously.

Any orally acceptable dosage form including, but not limited to,capsules, tablets, aqueous suspensions or solutions, can be used for theoral administration. In the case of tablets for oral use, carrierscommonly used include, but are not limited to, lactose and corn starch.Lubricating agents, such as magnesium stearate, are also typicallyadded. For oral administration in a capsule form, useful diluentsinclude lactose and dried cornstarch. When aqueous suspensions arerequired for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds(the compounds described above), the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof. Besides inert diluents, the oral compositions can alsoinclude adjuvants such as wetting agents, emulsifying and suspendingagents, sweetening, flavoring, and perfuming agents.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

Sterile injectable forms may be aqueous or oleaginous suspension. Thesesuspensions may be formulated according to techniques known in the artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents which arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms mayalso be used for the purposes of formulation.

In order to prolong the effect of the active compounds administered, itis often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are specificallysuppositories which can be prepared by mixing the active compound withsuitable non-irritating excipients or carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Dosage forms for topical or transdermal administration includeointments, pastes, creams, lotions, gels, powders, solutions, sprays,inhalants or patches. The active component is admixed under sterileconditions with a pharmaceutically acceptable carrier and any neededpreservatives or buffers as may be required. Ophthalmic formulation,eardrops, and eye drops are also contemplated as being within the scopeof this invention. Additionally, transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody, can also be used. Such dosage forms can be made by dissolving ordispensing the compound in the proper medium. Absorption enhancers canalso be used to increase the flux of the compound across the skin. Therate can be controlled by either providing a rate controlling membraneor by dispersing the compound in a polymer matrix or gel.

Alternatively, the compounds described above and pharmaceuticallyacceptable compositions thereof may also be administered by nasalaerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other conventional solubilizing or dispersingagents.

The compounds described above and pharmaceutically acceptablecompositions thereof can be formulated in unit dosage form. The term“unit dosage form” refers to physically discrete units suitable asunitary dosage for subjects undergoing treatment, with each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, optionally in association with asuitable pharmaceutical carrier. The unit dosage form can be for asingle daily dose or one of multiple daily doses (e.g., about 1 to 4 ormore times per day). When multiple daily doses are used, the unit dosageform can be the same or different for each dose. The amount of theactive compound in a unit dosage form will vary depending upon, forexample, the host treated, and the particular mode of administration,for example, from 0.01 mg/kg body weight/day to 100 mg/kg bodyweight/day.

EXEMPLIFICATION Example 1 Methyl4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl]amino)-3-methoxybenzoate

Method A: Methyl 3-(cyclopentylamino)-2,2-dimethylpropanoatehydrochloride

1,3,5-tricyclopentyl-1,3,5-triazinane (112.9 g, 387.3 mmol) and(1-methoxy-2-methyl-prop-1-enoxy)-trimethyl-silane (202.6 g, 1.162 mol)in DCM (1 L) was stirred at 0° C. followed by dropwise addition oftrifluoromethanesulfonic acid (4 mL, 45 mmol). The mixture was stirredat ambient temperature overnight. Mixture was diluted with sat.bicarbonate aqueous solution and extracted twice with DCM. Organicslayers were combined, washed with brine, dried (MgSO4), filtered andsolvents removed to leave a reddish mobile oil which was filteredthrough a silica plug (800 ml silica) eluting with 0-5% MeOH:EtOAc.

This mobile red oil was dissolved in ether (500 ml) cooled to 0° C.,followed by slow addition of HCl in ether and stirred for 2 hours.Petroleum ether (500 ml) was added and pink solid isolated by filtration(160.62 g). The mother liquors were concentrated and the addition of HClin ether repeated and pink solid was isolated as before. Solids combinedto give methyl 3-(cyclopentylamino)-2,2-dimethylpropanoate hydrochlorideas a slightly pink solid (255.35 g, 92%). NMR CDCl₃ 1.45 (6H, s),1.6-1.67 (2H, m), 1.87-1.97 (2H, m), 2.0-2.1 (2H, m), 2.1-2.2 (2H, m),3.08 (2H, s), 3.50-3.57 (1H, m), 3.77 (3H, s)

Method B: tert-butyl 3-(cyclopentylamino)-2,2-dimethylpropanoate

Methyl 3-(cyclopentylamino)-2,2-dimethyl-propanoate hydrochloride (3 g,12.73 mmol) was dissolved in DCM and washed with aqueous bicarbonatesolution, then brine and concentrated to an oil. This oil was dissolvedin THF (10 ml) and added to a 1M solution of potassium butoxide (12.73mL of 1 M, 12.73 mmol) in THF at 0° C. Reaction mixture turned to thickpaste and was diluted with THF (20 ml) and stirred at ambienttemperature for 1 hr. A further 2 ml of 1M butoxide added and stirredfor 1 hr. The mixture was concentrated to a paste, diluted withethylacetate and washed with water (×2), brine and concentrated to givetert-butyl 3-(cyclopentylamino)-2,2-dimethylpropanoate as an oil (2.6 g,85%). NMR CDCl₃ 1.18-1.2 (6H, m), 1.27-1.35 (2H, m), 1.46 (9H, s),1.50-1.58 (2H, m), 1.63-1.72 (2H, m), 1.78-1.87 (2H, m), 2.62 (2H, s),3.02-3.08 (1H, m); MS (ES+) 242.1

Method C: tert-butyl3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-dimethylpropoate

tert-butyl 3-(cyclopentylamino)-2,2-dimethyl-propanoate (21.44 g, 76.39mmol) was suspended in petroleum ether (296.4 mL): DCM (118.6 mL) andsodium bicarbonate (25.67 g, 305.6 mmol) were added. The reactionmixture was cooled to 0° C. and 2,4-dichloro-5-nitro-pyrimidine (14.82g, 76.39 mmol) was added portionwise. The mixture was stirred at ambienttemperature overnight. The mixture was filtered to remove inorganics,concentrated to give a viscous yellow oil and purified by columnchromatography (800 ml silica) eluting with 5% ethyl acetate: petrol.The oil thus obtained oil was dissolved in ether and triturated withpetroleum ether to give tert-butyl 3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-dimethylpropoate as a yellow crystalline solid(24.4 g, 80%). NMR CDCl₃ 1.18 (6H, s), 1.46 (9H, s), 1.52-1.58 (2H, m),1.63-1.70 (2H, m), 1.72-1.80 (2H, m), 1.92-1.98 (2H, m), 2.62 (2H, s),3.58-3.65 (1H, m), 3.92 (2H, s), 8.9 (1H, s); MS (ES+) 399.1

Method D: Methyl 4-(4-((3-tert-butoxy-2,2-dimethyl-3-oxopropyl)(cyclopentyl)amino)-5-nitropyridin-2-ylamino)-3-methoxybenzoate

tert-butyl3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dimethyl-propanoate(1.5 g, 3.760 mmol), methyl 4-amino-3-methoxy-benzoate (817.5 mg, 4.512mmol) and DIPEA (728.9 mg, 982.3 μL, 5.640 mmol) in 4-methylpentan-2-olwere treated under microwave at 140 C for 2 hours. The mixture wasconcentrated and purification by flash chromatography, eluting with 5%ethylacetate/petether to remove impurities followed by 10%ethylacetate/pet ether to elute product, gave methyl4-(4-((3-tert-butoxy-2,2-dimethyl-3-oxopropyl)(cyclopentyl)amino)-5-nitropyridin-2-ylamino)-3-methoxybenzoate as ayellow oil (1.25 g, 61%). NMR CDCl₃ 1.18 (6H, s), 1.46 (9H, s),1.52-1.58 (2H, m), 1.63-1.70 (2H, m), 1.72-1.80 (2H, m), 1.92-1.98 (2H,m), 3.62-3.68 (1H, m), 3.85-4.0 (8H, m), 7.55 (1H, s), 7.72-7.75 (1H,m), 8.12 (1H, brs), 8.5 (1H, d), 8.97 (1H, s); MS (ES+) 544.1 (ES−)542.1

Method E: Methyl4-(9-cyclopentyl-7,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b[1,4]diazpine-2-ylamino0-3-methoxybenzoate

Methyl4-(4-((3-tert-butoxy-2,2-dimethyl-3-oxopropyl)(cyclopentyl)amino)-5-nitropyridin-2-ylamino)-3-methoxybenzoate(1.2 g, 2.207 mmol) in DCM (15 mL) was treated with dropwise addition ofTFA (5.033 g, 3.401 mL, 44.14 mmol). The mixture was stirred at rt for 3hours and concentrated to an oil, redissolved in DCM and concentrated.This process was repeated until a yellow solid was obtained. This solidwas suspended in acetic acid (20 mL) and Fe (184.8 mg, 3.310 mmol) wasadded. The mixture was heated to 60° C. for 1 hour, filtered throughcelite and concentrated. Purification by flash chromatography on silicagel, eluting with 2% methanol/DCM to remove impurities followed by 15%methanol/DCM, gave methyl4-(9-cyclopentyl-7,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-2-ylamino-3-methoxybenzoateas a pale yellow solid (650 mg, 67%). NMR CDCl₃ 1.32 (6H, s), 1.52-1.62(2H, m), 1.72-1.85 (4H, m), 2.02-2.08 (2H, m), 3:32 (2H, s), 3.92 (3H,s), 3.98 (3H, s), 5.32-5.4 (1H, m), 7.23-7.26 (1H, brs), 7.55 (1H, s),7.72-7.77 (3H, m), 8.53 (1H, d); MS (ES+) 440.1

Method F: Methyl4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoate

Methyl4-(9-cyclopentyl-7,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-2-ylamino-3-methoxybenzoateand dicesium carbonate (118.6 mg, 0.3640 mmol) were mixed in DMF. MeI(103.3 mg, 45.31 μL, 0.7280 mmol) was then added and the reactionmixture was stirred at room temperature overnight. The mixture wasdiluted with ethylacetate, filtered through small pad of celite, washedtwice with water, dried and concentrated to a yellow solid. Purificationby flash chromatography on silica gel, eluting with 1% methanol/DCM,gave methyl4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoateas a pale yellow solid (47 mg, 56%). NMR CDCl₃ 1.25 (6H, s), 1.53-1.58(2H, m), 1.69-1.83 (4H, m), 2.02-2.08 (2H, m), 3.33 (3H, s), 3.4 (2H,s), 3.92 (3H, s), 3.98 (3H, s), 5.27-5.34 (1H, m), 7.23-7.26 (1H, brs),7.55 (1H, s), 7.72-7.77 (2H, m), 7.88 (1H, s), 8.56 (1H, d); MS (ES+)454.1 (ES−) 452.1

Method G: 3-(Cyclopentylamino)-N,2,2,2-trimethylpropanamide

Methyl 3-(cyclopentylamino)-2,2-dimethyl-propanoate hydrochloride (3 g,12.73 mmol) was dissolved in methanamine, 33 wt % in EtOH (15 mL) andheated to 90° C. in a sealed tube overnight. The reaction was allowed tocool to ambient temperature and the solvent removed in vacuo. The crudeproduct was purified by column chromatography (0-5% MeOH/EtOAc+1% NH4OH)to give the sub-title compound as a colourless oil (1.18 g, 47%); 1H NMR(400.0 MHz, DMSO) d 1.02 (s, 6H), 1.22-1.33 (m, 2H), 1.39-1.51 (m, 2H),1.53-1.72 (m, 2H), 2.48 (s, 4H), 2.56 (d, J=4.5 Hz, 3H), 2.89-2.96 (m,1H) and 8.07 (br s, 1H); MS ES(+) 199.1, ES (−) not seen.

Method H:3-[(5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-N,2,2-trimethyl-propanamide

3-(cyclopentylamino)-N,2,2-trimethyl-propanamide (665 mg, 3.353 mmol)and 5-bromo-2,4-dichloro-pyrimidine (666 mg, 373.7 μL, 2.921 mmol) weredissolved in EtOH (10 mL) and DIPEA (511.4 mg, 691.9 μL, 3.957 mmol) wasadded. The reaction was allowed to stir at reflux temperature overnight.The solvent was removed in vacuto. The crude residue was purified bycolumn chromatography (0-100% EtOAc/Petrol) to give the sub-titleproduct as a brown oil (266 mg, 23%); ¹H NMR (400.0 MHz, DMSO) d 1.03(s, 6H), 1.54-1.83 (m, 8H), 2.57 (s, 3H), 3.68 (s, 2H), 4.23 (quin, 1H),7.53 (d, 1H), 8.63 (s, 1H); MS ES(+) 391.0, ES (−) 389.0.

Method I: Methyl4-(5-bromo-4-(cyclopentyl(2,2-dimethyl-3-(methylamino)-3-oxopropyl)amino)pyrimidin-2-ylamino)-3-methoxybenzoate

3-[(5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amino]-N,2,2-trimethyl-propanamide(266 mg, 0.6825 mmol) and methyl 4-amino-3-methoxy-benzoate (185.5 mg,1.024 mmol) were dissolved in EtOH (2 mL) and Water (8 mL) and treatedwith HCl (134.5 μL of 37% w/v, 1.365 mmol). Heat at 90° C. overnight.Cool to ambient temperature and remove solvent in vacuo. The reactionmixture was diluted with EtOAc/NaHCO3 and extracted with EtOAc. Thecombined organic extracts were dried (Na2SO4), filter and concentrated.The crude residue was purified by column chromatography (0 to 100%EtOAc/Petrol) to give the sub-title compound as a beige oil (84 mg,23%); NMR (400.0 MHz, DMSO) d 0.97 (s, 6H), 1.44-1.69 (m, 8H), 2.45 (d;J=4.4 Hz, 3H), 3.58 (br s, 2H), 3.84 (s, 3H), 3.96 (s, 3H), 4.11 (quin,1H), 7.32-7.34 (m, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.61 (d, 1H), 8.07 (s,1H), 8.38 (s, 1H) and 8.43 (d, J=8.5 Hz, 1H); MS ES(+) 536.0, ES (−)534.1.

Method J: Methyl4-[(9-cyclopentyl-5,7,7-trimethyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-benzoate

Methyl4-(5-bromo-4-(cyclopentyl(2,2-dimethyl-3-(methylamino)-3-oxopropyl)amino)pyrimidin-2-ylamino)-3-methoxybenzoate(84 mg, 0.1572 mmol) and Cs2CO3 (74.25 mg, 0.2279 mmol) were dissolvedin dioxane (2 mL) and Pd2(dba)₃ (4.319 mg, 0.004716 mmol) and Xantphos(7.279 mg, 0.01258 mmol) were added. Heat to 100° C. overnight. TheXantphos and Pd2(dba)3 were replenished and the reaction heated undermicrowave conditions (120° C. for 30 minutes.) The solvent was removedin vacuo and the crude residue purified by column chromatography (0 to100% EtOAc/Petrol) to give the title compound as a beige solid (42 mg,59%); ¹H NMR (400.0 MHz, DMSO) d 1.25 (s, 6H), 1.72-1.82 (m, 4H),1.85-1.95 (m, 2H), 1.98-2.04 (m, 2H), 3.35 (s, 3H), 3.54 (s, 2H), 3.99(s, 3H), 4.11 (s, 3H), 5.34 (quin, 1H), 7.66 (s, 1H), 7.74 (d, 1H), 7.98(s, 1H), 8.17 (s, 1H) and 8.64 (d, 1H); MS ES(+) 454.1, ES (−) 452.1.

All references provided herein are incorporated herein in its entiretyby reference. As used herein, all abbreviations, symbols and conventionsare consistent with those used in the contemporary scientificliterature. See, e.g., Janet S: Dodd, ed., The ACS Style Guide: A Manualfor Authors and Editors, 2nd Ed., Washington, D.C.: American ChemicalSociety, 1997.

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1. A method of preparing a compound represented by Structural Formula(I), or a pharmaceutically acceptable salt thereof:

wherein: R¹ is —H, C₁₋₆ aliphatic, C₃₋₁₀cycloaliphatic, C₆₋₁₀ aryl, 5-10membered heteroaryl, or 3-10 membered heterocyclyl, wherein each of saidaliphatic, cycloaliphatic, aryl, heteroaryl, and heterocyclyl groupsrepresented by R¹ is optionally and independently substituted with oneor more instances of J¹; each R², R³, R⁴, and R⁵ is independently —H,halogen, cyano, C₁₋₆ aliphatic, or C₃₋₁₀ cycloaliphatic, wherein each ofsaid aliphatic and cycloaliphatic groups represented by R², R³, R⁴, andR⁵, respectively, is optionally and independently substituted with oneor more instances of J², J³, J⁴, and J⁵, respectively; optionally, R²and R³, together with the carbon atom to which they are attached, form aC₃₋₇ cycloaliphatic ring that is optionally substituted with one or moreinstances of J^(B); optionally, R³ and R⁴, together with the carbonatoms to which they are attached, form a C₃₋₇ cycloaliphatic ring thatis optionally substituted with one or more instances of J^(B);optionally, R⁴ and R⁵, together with the carbon atom to which they areattached, form a C₃₋₇ cycloaliphatic ring that is optionally substitutedwith one or more instances of J^(B); R⁶ is —H, C₁₋₆ aliphatic, C₃₋₁₀cycloaliphatic, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or 3-10 memberedheterocyclyl, wherein each of said aliphatic, cycloaliphatic, aryl,heteroaryl, and heterocyclyl groups represented by R⁶ is optionally andindependently substituted with one or more instances of J⁶; R⁷ is —H,C₁₋₆ aliphatic optionally substituted with one or more instanced ofJ^(A), or C₃₋₈ cycloaliphatic optionally substituted with one or moreinstanced of J^(B); or, optionally R⁷, together with R¹ and the nitrogenatom to which it is attached, forms a 5-7 membered heterocyclic ringthat is optionally substituted with one or more instances of J^(B); andR⁸ is —H or R⁹; R⁹ is C₁₋₆ aliphatic or C₃₋₈cycloaliphatic, wherein saidaliphatic group is independently and optionally substituted with one ormore instances of J^(A), and wherein said cycloaliphatic group isindependently and optionally substituted with one or more instances ofJ^(B); each J¹ is independently T or C₁₋₆ aliphatic optionallysubstituted with one or more instances of T; each of J², J³, J⁵, and J⁶is independently M, or C₁₋₆ aliphatic optionally substituted with one ormore instances of M; each T is independently halogen, oxo, —NO₂, —CN,Q¹, —Z¹—H, or —Z²-Q²; each Z¹ is independently a unit consisting of oneor more groups independently selected from the group consisting of —NR—,—O—, —S—, —C(O)—, —C(═NR)—, —C(═NOR)—, and —SO₂N(R)—; each Z² isindependently a unit consisting of one or more groups independentlyselected from the group consisting of —NR—, —O—, —S—, —C(O)—, —C(═NR)—,—C(═NOR)—, —S(O)—, and —S(O)₂—; each Q¹ is independently C₃₋₁₀cycloaliphatic, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or 3-10 memberedheterocyclyl, wherein each Q¹ is independently and optionallysubstituted with one or more instances of J^(Q); each Q² isindependently C₁₋₆ aliphatic, C₃₋₁₀ cycloaliphatic, C₆₋₁₀ aryl, 5-10membered heteroaryl, 3-10 membered heterocyclyl, or Q¹-Q¹, each of whichis optionally and independently substituted with one or more instancesof J^(Q); or each Q², together with R and the nitrogen atom to which itis attached, optionally forms a 4-7 membered heterocyclic ringoptionally substituted with one or more instances of J^(B); and eachJ^(Q) is independently M or C₁₋₆ aliphatic optionally substituted withone or more instances of M; each M is independently halogen, oxo, —NO₂,—CN, —OR′, —SR′, —N(R′)₂, —COR″, —CO₂R′, —CONR′₂, —OCOR″, —OCON(R′)₂,—NRCOR′, —NRCO₂R′, —NRCON(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂, —NRSO₂R″,—NRSO₂N(R′)₂, C₃₋₁₀ cycloaliphatic, 3-10 membered heterocyclyl, C₆₋₁₀aryl, or 5-10 membered heteroaryl, wherein each of said cycloaliphatic,heterocyclyl, aryl and heteroaryl groups represented by M is optionallyand independently substituted with one or more instances of J^(B); eachR is independently —H or C₁₋₆ aliphatic, or each R, together with Q² andthe nitrogen atom to which it is attached, optionally forms a 4-7membered heterocyclic ring optionally being substituted with one or moreinstances of J^(B); each R′ is independently —H or C₁₋₆ aliphaticoptionally substituted with one or more instances of J^(A); or two R′groups, together with the nitrogen atom to which they are attached, forma 4-7 membered heterocyclic ring optionally being substituted with oneor more instances of J^(B); each R″ is independently C₁₋₄ aliphaticoptionally substituted with one or more instances of J^(A); each J^(A)is independently selected from the group consisting of halogen, oxo,—CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl),—CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), —O(C₁-C₄ alkyl), C₃₋₇cycloalkyl, and C₃₋₇cyclo(haloalkyl); each J^(B) is independentlyselected from the group consisting of halogen, oxo, —CN, —OH, —NH₂,—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),—CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄ alkyl), and C₁-C₄ aliphatic that isoptionally substituted with one or more instances of J^(A); and q is 0or 1; comprising the steps of: a) reacting a compound represented byStructural Formula (A):

with HNR¹R⁷ under suitable conditions to form a compound represented byStructural

Formula (B): wherein: R¹¹ is —NHR¹³, and R¹² is halogen; or R¹¹ is—OR¹⁴, and R¹² is —NO₂; and R¹³ is —H or R⁹; R¹⁴ is C₁₋₆ alkyl; and LG₁is a suitable leaving group; and b) i) when R¹² is —NO₂, and R¹¹ is—OR¹⁴: 1) cyclizing the compound represented by Structural Formula (B)under suitable cyclisation conditions to form a compound represented byStructural Formula (II):

2) optionally reacting the compound represented by Structural Formula(II) with R⁹-LG₂, wherein LG₂ is a suitable leaving group, to form thecompound represented by Structural Formula (I), wherein R⁸ is other than—H; or ii) when R¹² is halogen, and R¹¹ is —NHR¹³: 1) cyclizing thecompound represented by Structural Formula (B) under suitablecyclisation conditions to form the compound represented by StructuralFormula (I); and 2) optionally, when R¹³ is —H, reacting the compoundproduced from step b), ii), 1) with R⁹-LG₂, wherein LG₂ is a suitableleaving group, to form the compound represented by Structural Formula(I), wherein R⁸ is other than —H.
 2. The method of claim 1, wherein R¹is optionally substituted Cl₆ aliphatic, optionally substituted C₆₋₁₀aryl, or optionally substituted 5-10 membered heteroaryl.
 3. The methodof claim 2, wherein R⁷ is —H, or optionally substituted C₁₋₆ aliphatic.4. The method of any one of claims 1-3, wherein R⁶ is —H, optionallysubstituted C₁₋₆ aliphatic, optionally substituted C₃₋₇cycloaliphatic,optionally substituted 3-7 membered heterocyclyl, optionally substitutedphenyl, or optionally substituted 5-6 membered heteroaryl.
 5. The methodof claim 1, wherein each of R², R³, R⁴ and R⁵ is independently —H,halogen, optionally substituted C₁₋₆ aliphatic, or optionallysubstituted C₃₋₇cycloaliphatic; or optionally R² and R³, R³ and R⁴, andR⁴ and R⁵, respectively, together with the atom to which they are bound,independently form an optionally substituted C₃₋₇cycloaliphatic ring. 6.The method of claim 5, wherein R⁸ is —H, or optionally substituted C₁₋₆aliphatic.
 7. The method of claim 1, further comprising the step ofreacting a compound represented by Structural Formula (C):

with a compound represented by Structural Formula (D):

to form the compound represented by Structural Formula (A), wherein LG₃is a suitable leaving group.
 8. The method of claim 7, wherein each ofLG₁ and LG₂ independently is halogen.
 9. The method of claim 8, whereinLG₁ and LG₂ are both —Cl.
 10. The method of claim 9, wherein R¹² is—NO₂, and R¹¹ is —OR¹⁴.
 11. The method of claim 10, wherein R¹⁴ is C₁₋₆alkyl.
 12. The method of claim 9, wherein R¹² is halogen, and R¹¹ is—NHR³.
 13. The method of claim 12, wherein R¹² is —Br or —I, and R¹³ isC₁₋₆ alkyl.
 14. The method of claim 13, wherein R¹² is —Br.
 15. Themethod of claim 9, wherein: each Z¹ is independently —N(R)—, —O—, —S—,—CO₂—, —C(O)N(R)—, —OC(O)N(R)—, —N(R)CO₂—, —N(R)C(O)N(R)—,—C(O)N(R)CO₂—, —SO₂N(R)—, or —N(R)SO₂N(R)—; and each Z² is independently—N(R)—, —O—, —S—, —CO₂—, —OC(O)—, —C(O)N(R)—, —N(R)C(O)—, —OC(O)N(R)—,—N(R)CO₂—, —N(R)C(O)N(R)—, —C(O)N(R)CO₂—, —S(O)₂—, —SO₂N(R)—, —N(R)SO₂—,or —N(R)SO₂N(R)—.
 16. The method of claim 15, wherein R¹ is C₁₋₄alkylsubstituted with Q¹ and optionally further substituted with one or moresubstituents independently selected from the group consisting ofhalogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), and—O(C₁-C₄ alkyl).
 17. The method of claim 15, wherein R¹ is C₆₋₁₀ aryl or5-6 membered heteroaryl, each optionally and independently substitutedwith one or more substituents independently selected from the groupconsisting of T and C₁₋₆ aliphatic optionally substituted with one ormore instances of T; and wherein each T is halogen, cyano, Q¹, —N(R)H,—OH, —SH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H, —SO₂N(R)H,—N(R)SO₂N(R)H, —S(O)₂Q², —N(R)Q², —OQ², —SQ², —CO₂Q², —OC(O)Q²,—C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q²,—N(R)C(O)N(R)Q², —SO₂N(R)Q², —N(R)SO₂Q², or —N(R)SO₂N(R)Q².
 18. Themethod of claim 16 or 17, wherein R⁷ is —H, or C₁₋₆ alkyl.
 19. Themethod of claim 18, wherein R⁶ is —H, optionally substituted C₁₋₆ alkyl,or optionally substituted C₃₋₇cycloalkyl.
 20. The method of claim 19,wherein R⁸ is —H, or C₁₋₆ alkyl.
 21. The method of claim 20, whereineach of R², R³, R⁴ and R⁵ is independently —H, or optionally substitutedC₁₋₆ alkyl; or optionally R² and R³, together with the atom to whichthey are bound, form an optionally substituted C₃₋₇cycloalkyl ring. 22.The method of claim 21, wherein: i) R² is —H or C₁₋₃alkyl; R³ is C₁₋₃alkyl; R⁴ is —H or C₁₋₃alkyl; and R⁵ is —H or C₁₋₃alkyl; or ii) R² andR³ together with the atom to which they are bound form a C₃₋₇ cycloalkylring; R⁴ is —H or C₁₋₃alkyl; and R^(S) is —H or C₁₋₃alkyl.
 23. Themethod of claim 22, wherein R⁴ and R⁵ are both —H.
 24. The method ofclaim 17, wherein R¹ is phenyl optionally substituted with one or moresubstituents independently selected from the group consisting of T andC₁₋₆ aliphatic optionally substituted with one or more instances of T;and wherein each T is halogen, cyano, —N(R)H, —OH, —CO₂H, —C(O)N(R)H,—OC(O)N(R)H, —N(R)Q², —OQ², —CO₂Q², —OC(O)Q², —C(O)N(R)Q², —N(R)C(O)Q²,—N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q², or —N(R)C(O)N(R)Q².
 25. Thecompound of claim 24, wherein R⁷ is —H.
 26. The method of claim 25,wherein R⁶ is optionally substituted C₃₋₆ cycloalkyl.
 27. The method ofclaim 26, wherein R¹ is optionally substituted aryl or optionallysubstituted heteroaryl.
 28. The method of claim 27, wherein q is
 1. 29.A method of preparing a compound by Structural Formula (III):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is —H, C₁₋₆aliphatic, C₃₋₁₀ cycloaliphatic, C₆₋₁₀ aryl, 5-10 membered heteroaryl,or 3-10 membered heterocyclyl, wherein each of said aliphatic,cycloaliphatic, aryl, heteroaryl, and heterocyclyl groups represented byR¹ is optionally and independently substituted with one or moreinstances of J¹; each R², R³, R⁴, and R⁵ is independently —H, halogen,cyano, C₁₋₆ aliphatic, or C₃₋₁₀ cycloaliphatic, wherein each of saidaliphatic and cycloaliphatic groups represented by R², R³, R⁴, and R⁵,respectively, is optionally and independently substituted with one ormore instances of J², J³, J⁴, and J⁵, respectively; optionally, R² andR³, together with the carbon atom to which they are attached, form aC₃₋₇ cycloaliphatic ring that is optionally substituted with one or moreinstances of J^(B); optionally, R³ and R⁴, together with the carbonatoms to which they are attached, form a C₃₋₇ cycloaliphatic ring thatis optionally substituted with one or more instances of J^(B);optionally, R⁴ and R^(S), together with the carbon atom to which theyare attached, form a C₃₋₇cycloaliphatic ring that is optionallysubstituted with one or more instances of J^(B); R⁶ is —H, C₁₋₆aliphatic, or C₃₋₁₀ cycloaliphatic, wherein each of said aliphatic andcycloaliphatic groups represented by R⁶ is optionally and independentlysubstituted with one or more instances of J⁶; R⁷ is —H, C₁₋₆ aliphaticoptionally substituted with one or more instanced of J^(A), or C₃₋₈cycloaliphatic optionally substituted with one or more instanced ofJ^(B); or, optionally R⁷, together with R¹ and the nitrogen atom towhich it is attached, forms a 5-7 membered heterocyclic ring that isoptionally substituted with one or more instances of J^(B); and R⁸ is —Hor R⁹; R⁹ is C₁₋₆ aliphatic, or C₃₋₈ cycloaliphatic, wherein saidaliphatic group is independently and optionally substituted with one ormore instances of J^(A), and wherein said cycloaliphatic group isindependently and optionally substituted with one or more instances ofJ^(B); each J¹ is independently T or C₁₋₆ aliphatic optionallysubstituted with one or more instances of T; each of J², J³, J⁴, J⁵, andJ⁶ is independently M, or C₁₋₆ aliphatic optionally substituted with oneor more instances of M; each T is independently halogen, oxo, —NO₂, —CN,Q¹, —Z¹—H, or —Z²-Q²; each Z¹ is independently a unit consisting of oneor more groups independently selected from the group consisting of —NR—,—O—, —S—, —C(O)—, —C(═NR)—, —C(═NOR)—, and —SO₂N(R)—; each Z² isindependently a unit consisting of one or more groups independentlyselected from the group consisting of —NR—, —O—, —S—, —C(O)—, —C(═NR)—,—C(═NOR)—, —S(O)—, and —S(O)₂—; each Q¹ is independently C₃₋₁₀cycloaliphatic, C₆₋₁₀ aryl, 5-10 membered heteroaryl, or 3-10 memberedheterocyclyl, wherein each Q¹ is independently and optionallysubstituted with one or more instances of J^(Q); each Q² isindependently C₁₋₆ aliphatic, C₃₋₁₀ cycloaliphatic, C₆₋₁₀ aryl, 5-10membered heteroaryl, 3-10 membered heterocyclyl, or Q¹-Q¹, each of whichis optionally and independently substituted with one or more instancesof J^(Q); or each Q², together with R and the nitrogen atom to which itis attached, optionally forms a 4-7 membered heterocyclic ringoptionally substituted with one or more instances of J^(B); and eachJ^(Q) is independently M or C₁₋₆ aliphatic optionally substituted withone or more instances of M; each M is independently halogen, oxo, —NO₂,—CN, —OR′, —SR′, —N(R′)₂, —COR′, —CO₂R′, —CONR′₂, —OCOR″, —OCON(R′)₂,—NRCOR′, —NRCO₂R′, —NRCON(R′)₂, —S(O)R″, —SO₂R″, —SO₂N(R′)₂, —NRSO₂R″,—NRSO₂N(R′)₂, C₃₋₁₀ cycloaliphatic, 3-10 membered heterocyclyl, C₆₋₁₀aryl, or 5-10 membered heteroaryl, wherein each of said cycloaliphatic,heterocyclyl, aryl and heteroaryl groups represented by M is optionallyand independently substituted with one or more instances of J^(B); eachR′ is independently —H or C₁₋₆ aliphatic, or each R, together with Q²and the nitrogen atom to which it is attached, optionally forms a 4-7membered heterocyclic ring optionally being substituted with one or moreinstances of J^(B); each R′ is independently —H or C₁₋₆ aliphaticoptionally substituted with one or more instances of J^(A); or two R′groups, together with the nitrogen atom to which they are attached, forma 4-7 membered heterocyclic ring optionally being substituted with oneor more instances of J^(B); each R″ is independently C₁₋₄ aliphaticoptionally substituted with one or more instances of J^(A); and eachJ^(A) is independently selected from the group consisting of halogen,oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄ alkyl),C₃₋₇cycloalkyl, and C₃₋₇cyclo(haloalkyl); each J^(B) is independentlyselected from the group consisting of halogen, oxo, —CN, —OH, —NH₂,—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),—CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄ alkyl), and C₁-C₄ aliphatic that isoptionally substituted with one or more instances of J^(A); comprisingthe steps of: a) reacting a compound represented by Structural Formula(A):

with HNR¹R⁷ under suitable conditions to form a compound represented byStructural

Formula (B): wherein: q is 1; R¹¹ is —NHR¹³, and R¹² is halogen; or R¹¹is —OR¹⁴, and R¹² is —NO₂; and R¹³ is H or R⁹; R¹⁴ is C₁₋₆ alkyl; andLG₁ is a suitable leaving group; and b) i) when R¹² is —NO₂, and R¹¹ is—OR¹⁴: 1) cyclizing the compound represented by Structural Formula (B)under suitable cyclisation conditions to form a compound represented byStructural Formula (II):

2) optionally reacting the compound represented by Structural Formula(II) with R⁹-LG₂, wherein LG₂ is a suitable leaving group, to form thecompound represented by Structural Formula (I) wherein R⁸ is R⁹; or ii)when R² is halogen, and R¹¹ is —NHR¹³: 1) cyclizing the compoundrepresented by Structural Formula (B) under suitable cyclisationconditions to form the compound represented by Structural Formula (I);and 2) optionally, when R¹³ is —H, reacting the compound produced fromstep b), ii), 1) with R⁹-LG₂, wherein LG₂ is a suitable leaving group,to form the compound represented by Structural Formula (I) wherein R⁸ isR⁹.
 30. The method of claim 29, wherein: R¹ is optionally substitutedC₆₋₁₀ aryl or optionally substituted 5-10 membered heteroaryl; each Z¹is independently —N(R)—, —O—, —S—, —CO₂—, —C(O)N(R)—, —OC(O)N(R)—,—N(R)CO₂—, —N(R)C(O)N(R)—, —C(O)N(R)CO₂—, —SO₂N(R)—, or —N(R)SO₂N(R)—;each Z² is independently —N(R)—, —O—, —S—, —CO₂—, —OC(O)—, —C(O)N(R)—,—N(R)C(O)—, —OC(O)N(R)—, —N(R)CO₂—, —N(R)C(O)N(R)—, —C(O)N(R)CO₂—,—S(O)—, —S(O)₂—, —SO₂N(R)—, —N(R)SO₂—, or —N(R)SO₂N(R)—; each Q¹independently is optionally substituted C₃₋₇cycloalkyl, optionallysubstituted phenyl, optionally substituted 5-6 membered heteroaryl, oroptionally substituted 4-7 membered heterocyclyl; each of R² and R³, R⁴and R⁵ is independently —H, halogen, cyano, or C₁₋₆ aliphatic, oroptionally R² and R³, R³ and R⁴, and R⁴ and R⁵, respectively, togetherwith the carbon atom(s) to which they are bound, independently form aC₃₋₇ cycloalkyl ring, wherein each of said aliphatic and cycloalkyl ringis independently and optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), and—O(C₁-C₄ alkyl); R⁶ is —H, C₁₋₆ aliphatic or C₃₋₇ cycloaliphatic, eachof which is optionally and independently substituted with one or moresubstituents independently selected from the group consisting ofhalogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), and—O(C₁-C₄ alkyl); and each of R⁷ and R⁸ is independently —H or C₁₋₆alkyl.
 31. The method of claim 30, wherein the compound produced by themethod is represented by Structural Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein: phenyl ring A isoptionally substituted with one or more substitutents independentlyselected from the group consisting of T and C₁₋₆ aliphatic optionallysubstituted with one or more instances of T; each T is halogen, cyano,Q¹, —N(R)H, —OH, —CO₂H, —C(O)N(R)H, —OC(O)N(R)H, —N(R)C(O)N(R)H,—SO₂N(R)H, —N(R)SO₂N(R)H, —S(O)₂Q², —N(R)Q², —OQ², —CO₂Q², —OC(O)Q²,—C(O)N(R)Q², —N(R)C(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², —C(O)N(R)CO₂Q²,—N(R)C(O)N(R)Q², —SO₂N(R)Q², —N(R)SO₂Q², or —N(R)SO₂N(R)Q²; Q¹ isC₃₋₇cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 memberedheterocyclyl, each optionally and independently substituted with one ormore substitutents independently selected from the group consisting ofhalogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂(C₁-C₄ alkyl), —O(C₁-C₄alkyl), C₁-C₄ alkyl, C₁-C₄ haloalkyl; C₁-C₄ cyanoalkyl, C₁-C₄aminoalkyl, C₁-C₄ hydroxyalkyl, and C₂-C₄ alkoxyalkyl; each Q² isindependently C₁₋₆ alkyl, C₃₋₇cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, or 4-7 membered heterocyclyl, or each Q², together with R,optionally and independently forms an optionally substituted, 4-7membered heterocyclic ring; wherein said C₁₋₆ alkyl represented by Q² isoptionally substituted with one or more substitutents independentlyselected from the group consisting of halogen, oxo, —CN, —OH, —NH₂,—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, —OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl),—CO₂H, —CO₂ (C₁-C₄ alkyl), and —O(C₁-C₄ alkyl); and wherein each of saidcycloalkyl, aryl, heteroaryl, and heterocyclyl groups represented by Q²is optionally and independently substituted with one or moresubstitutents independently selected from the group consisting ofhalogen, oxo, —CN, —OH, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂,—OCO(C₁-C₄ alkyl), —CO(C₁-C₄ alkyl), —CO₂H, —CO₂ (C₁-C₄ alkyl), —O(C₁-C₄alkyl), C₁-C₄ alkyl, C₁-C₄ haloalkyl; C₁-C₄ cyanoalkyl, C₁-C₄aminoalkyl, C₁-C₄ hydroxyalkyl, and C₂-C₄ alkoxyalkyl; each of R² and R³is independently —H, halogen, or optionally substituted C₁₋₆ aliphatic;or optionally R² and R³, together with the carbon atom to which they areattached, form an optionally substituted C₃₋₆cycloalkyl ring; and R⁶ isoptionally substituted —H, optionally substituted C₁₋₆ alkyl, oroptionally substituted C₃₋₆cycloalkyl.
 32. The method of claim 31,wherein R⁶ is C₅₋₆cycloalkyl.
 33. The method of claim 32, wherein: i) R²is —H or C₁₋₃ alkyl; and R³ is C₁₋₃alkyl; or ii) R² and R³ together withthe atom to which they are bound form a C₃₋₆ cycloalkyl ring.
 34. Themethod of any one of claims 31-33, wherein phenyl ring A is substitutedwith one or more substituents independently selected from the groupconsisting of —C(O)N(R)H, —C(O)N(R)Q², —N(R)C(O)Q², —CO₂H, —CO₂Q²,—OC(O)Q², —N(R)CO₂Q², —OC(O)N(R)Q², and —N(R)C(O)N(R)Q²; and optionallyfurther substituted with one or one or more substituents independentlyselected from the group consisting of halogen, —CN, —OH, —NH₂, —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)₂, —O(C₁-C₄ alkyl), C₁-C₄ alkyl, C₁-C₄ haloalkyl;C₁-C₄ cyanoalkyl, C₁-C₄ aminoalkyl, C₁-C₄ hydroxyalkyl, and C₂-C₄alkoxyalkyl.
 35. The method of claim 34, wherein phenyl ring A issubstituted with —OC(O)Q², —C(O)N(R)Q²; or —N(R)C(O)Q², and optionallyfurther substituted with one or one or more substituents independentlyselected from the group consisting of halogen, —CN, —OH, —NH₂, —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)₂, —O(C₁-C₄ alkyl), C₁-C₄ alkyl, C₁-C₄ haloalkyl;C₁-C₄ cyanoalkyl, C₁-C₄ aminoalkyl, C₁-C₄ hydroxyalkyl, and C₂-C₄alkoxyalkyl.
 36. The method of claim 1, wherein the compound of Formula(I) is represented by any one of the following structural formulae:

or a pharmaceutically acceptable salt thereof.
 37. The method of claim1, wherein the compound of Structural Formula (I) is represented by anyone of the following structural formulae:

or a pharmaceutically acceptable salt thereof.
 38. The method of claim1, wherein the compound produced by the method is represented by any oneof the following structural formulae:

or a pharmaceutically acceptable salt thereof.
 39. The method of claim1, wherein the compound represented by Structural Formula (I) isrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof.
 40. The method of claim1, wherein the compound represented by Structural Formula (I) isrepresented by the following structural formula:

or a pharmaceutically acceptable salt thereof.